Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
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Variant: NM_004999.3(MYO6):c.238C>T (p.Arg80Ter)

CA183381

178957 (ClinVar)

Gene: MYO6
Condition: nonsyndromic genetic deafness
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 55e341ba-860e-45fd-b865-3fe4a6086732

HGVS expressions

NM_004999.3:c.238C>T
NM_004999.3(MYO6):c.238C>T (p.Arg80Ter)
NC_000006.12:g.75828590C>T
CM000668.2:g.75828590C>T
NC_000006.11:g.76538307C>T
CM000668.1:g.76538307C>T
NC_000006.10:g.76595027C>T
NG_009934.1:g.84399C>T
NG_009934.2:g.84398C>T
ENST00000369975.6:c.238C>T
ENST00000369977.8:c.238C>T
ENST00000369985.9:c.238C>T
ENST00000462633.3:c.238C>T
ENST00000627432.3:c.238C>T
ENST00000653423.1:c.238C>T
ENST00000653917.1:c.238C>T
ENST00000660420.1:c.*194C>T
ENST00000662184.1:c.238C>T
ENST00000662603.1:c.238C>T
ENST00000663400.1:c.238C>T
ENST00000664209.1:c.238C>T
ENST00000664640.1:c.238C>T
ENST00000671923.1:c.238C>T
ENST00000672093.1:n.238C>T
ENST00000369975.5:c.238C>T
ENST00000369977.7:c.238C>T
ENST00000369981.7:c.238C>T
ENST00000369985.8:c.238C>T
ENST00000615563.4:c.238C>T
ENST00000627432.2:c.238C>T
NM_001300899.1:c.238C>T
NM_004999.4:c.238C>T
NM_001300899.2:c.238C>T
NM_001368136.1:c.238C>T
NM_001368137.1:c.238C>T
NM_001368138.1:c.238C>T
NM_001368139.1:c.238C>T
NM_001368140.1:c.238C>T
NM_001368865.1:c.238C>T
NM_001368866.1:c.238C>T
NR_160538.1:n.470C>T
NR_160539.1:n.570C>T
NM_004999.4(MYO6):c.238C>T (p.Arg80Ter)

Pathogenic

Met criteria codes 4
PVS1 PP1 PS4_Supporting PM2_Supporting
Not Met criteria codes 22
BA1 BS2 BS3 BS4 BS1 BP7 BP5 BP3 BP1 BP4 BP2 PS1 PS3 PS2 PP2 PP3 PP4 PM6 PM4 PM5 PM1 PM3

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CDH23, COCH, GJB2, KCNQ4, MYO6, MYO7A, SLC26A4, TECTA and USH2A Version 2

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Hearing Loss VCEP
The NM_004999.4:c.238C>T (p.Arg80Ter) variant in MYO6 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 4 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0008% (1/113330 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Hearing Loss VCEP threshold (≤0.002%) for PM2_Supporting. This variant has been reported in 2 families with teenage onset progressive sensorineural hearing loss, both displaying an autosomal dominant pattern of inheritance (PS4_Supporting; PMID: 32143290, 33111345). The variant has been reported to segregate with hearing loss in 2 affected family members from 1 family (PP1; PMID:33111345). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal dominant hearing loss, based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss Variant Curation Expert Panel: (PVS1, PM2_Supporting, PS4_Supporting, PP1). (VCEP specifications version 2.0.0; December 21, 2022)
Met criteria codes
PVS1
Clinical validity classification of gene is Definitive and 3 or more LOF variants have been previously reported in the gene across more than 1 exon.
PP1
PMID: 33111345 - identified in family DF305 - proband with teenage onset, nonsyndromic, moderate high tone hearing loss, progressive. Variant segregated in two affected family members
PS4_Supporting
PMID: 32143290 - Identified in family OLD5048, in proband with progressive SNHL (55db), onset at 18yo. Dominant family history per pedigree (fig 1), but segregation not performed. PMID: 33111345 - identified in family DF305 - proband with teenage onset, nonsyndromic, moderate high tone hearing loss, progressive. Variant segregated in two affected family members. total of 2 probands from these papers.
PM2_Supporting
1/113330, 0.000008 alleles European (non-Finnish), gnomAD v.2.1.1
Not Met criteria codes
BA1
The p.Arg80X variant is in 0.0009% (1/111322) of European chromosomes in gnomAD.
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
The p.Arg80X variant is in 0.0009% (1/111322) of European chromosomes in gnomAD.
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Approved on: 2023-01-24
Published on: 2023-02-06
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