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Deafness, Autosomal Dominant 36 (DFNA36) and Deafness, Autosomal Recessive 7 (DFNB7) via the TMC1 Gene

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
11751 TMC1 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
11751TMC181479 81479(x2) $890 Order Options and Pricing

Pricing Comments

Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based tests. However, if full gene Sanger sequencing is desired for STAT turnaround time, insurance, or other reasons, please see link below for Test Code, pricing, and turnaround time information. If the Sanger option is selected, CNV detection may be ordered through Test #600.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

Click here for costs to reflex to whole PGxome (if original test is on PGxome Sequencing backbone).

Click here for costs to reflex to whole PGnome (if original test is on PGnome Sequencing backbone).

The Sanger Sequencing method for this test is NY State approved.

For Sanger Sequencing click here.

Turnaround Time

18 days on average for standard orders or 13 days on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

EMAIL CONTACTS

Genetic Counselors

Geneticist

  • Ben Dorshorst, PhD

Clinical Features and Genetics

Clinical Features

Autosomal dominant deafness 36 (DFNA36) is characterized by flat or gently downsloping, progressive, postlingual, sensorineural nonsyndromic hearing loss (Kurima et al. 2002). This disorder generally starts within the first two decades of life, eventually progressing to profound deafness within 10 to 15 years (Hilgert et al. 2009; Zhao et al. 2014). Autosomal recessive deafness 7 (DFNB7) is characterized by severe to profound, stable, prelingual, sensorineural nonsyndromic hearing loss (Scott et al. 1996). The audioprofile of most nonsyndromic hearing loss cases can be distinct, thus assisting in the development of an evaluation strategy for molecular genetic testing and in generating a prognosis on the rate of hearing loss per year (Hildebrand et al. 2008).

Genetics

DFNA36, an autosomal dominant hearing disorder, and DFNB7, an autosomal recessive hearing disorder, are caused by pathogenic sequence variants in the transmembrane channel-like (TMC1) gene, which is a member of the novel TMC gene family. Seven other TMC1 paralogs have been detected in various mammalian species (Davies et al. 2012). The TMC1 gene has been localized to chromosomal region 9q13-q21 and consists of 24 exons (Scott et al. 996). The function of the TMC1 protein remains obscure, although in silico analysis predicts that it is an integral membrane protein with six membrane-spanning domains (Drury et al. 2003). This protein topology has been confirmed in hair cells of the mouse inner ear, thus suggesting that it functions as a channel, receptor, or pump (Kawashima et al. 2011; Zhao et al. 2014). To date, a total of about 60 pathogenic TMC1 sequence variants have been reported, which include missense/nonsense, splicing, regulatory, small deletions, small insertions, and gross deletions (Human Gene Mutation Database). Only two dominant pathogenic sequence variants have been reported in the TMC1 gene (p.G417R and p.D572N), and studies have suggested that these variants cause disease in a dominant-negative or gain-of-function mechanism, instead of haploinsufficiency. Pathogenic missense variants at other positions in the gene apparently result in the creation of a functional null allele that would only cause hearing loss in the compound heterozygous or homozygous state (Kurima et al. 2002; Yang et al. 2010).

Clinical Sensitivity - Sequencing with CNV PGxome

Reported clinical sensitivity of the TMC1 test ranges from 0.1% to 8%. For example, in Japan, 0.09% (1/1,120) of nonsyndromic hearing loss cases were caused by pathogenic sequence variants in the TMC1 gene (Nishio and Usami 2015). In a Pakistani study, 3.3% (1/30) of families with autosomal recessive nonsyndromic hearing loss harbored disease-causing TMC1 sequence variants (Shafique et al. 2014). On the other hand, pathogenic TMC1 sequence variants were detected in 5% (1/20) of consanguineous families with autosomal recessive nonsyndromic hearing loss from Turkey and Iran (Diaz-Horta et al. 2012). In another study conducted in Turkey, 8% (4/49) of consanguineous families with nonsyndromic deafness were determined to harbor causative variants in the TMC1 gene (Duman et al. 2011).

Testing Strategy

This test provides full coverage of all coding exons of the TMC1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).

Indications for Test

Ideal TMC1 test candidates are individuals who present with autosomal dominant or recessive nonsyndromic hearing loss. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in TMC1.

Gene

Official Gene Symbol OMIM ID
TMC1 606706
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Citations

  • Davies K.T. et al. 2012. Heredity. 108: 480-9. PubMed ID: 22167055
  • Diaz-Horta O. et al. 2012. Plos One. 7: e50628. PubMed ID: 23226338
  • Drury S.S., Keats B.H. 2003. Journal of the American Academy of Audiology. 14: 296-301. PubMed ID: 14552423
  • Duman D. et al. 2011. Genetics Testing and Molecular Biomarkers. 15: 29-33. PubMed ID: 21117948
  • Hildebrand M.S. et al. 2008. Genetics in Medicine. 10: 797-804. PubMed ID: 18941426
  • Hilgert N. et al. 2009. Journal of Human Genetics. 54: 188-90. PubMed ID: 19180119
  • Human Gene Mutation Database (Bio-base).
  • Kawashima Y. et al. 2011. The Journal of Clinical Investigation. 121: 4796-809. PubMed ID: 22105175
  • Kurima K. et al. 2002. Nature Genetics. 30: 277-84. PubMed ID: 11850618
  • Nishio N.Y, Usami 2.. 2015. The Annals of Otology, Rhinology, and Laryngology. 124 Suppl 1: 49S-60S. PubMed ID: 25788563
  • Scott D.A. et al. 1996. American Journal of Human Genetics. 59: 385-91. PubMed ID: 8755925
  • Shafique S. et al. 2014. PLoS ONE. 9: e100146. PubMed ID: 24949729
  • Yang T. et al. 2010. Clinical Genetics. 77: 395-8. PubMed ID: 20447146
  • Zhao Y. et al. 2014. PLoS ONE. 9: e97064. PubMed ID: 24827932

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page


Specimen Types

Specimen Requirements and Shipping Details

PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

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ORDER OPTIONS

View Ordering Instructions

1) Select Test Method (Backbone)


1) Select Test Type


2) Select Additional Test Options

STAT and Prenatal Test Options are not available with Patient Plus.

No Additional Test Options are available for this test.

Note: acceptable specimen types are whole blood and DNA from whole blood only.
Total Price: $
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