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]
Link to SEPIO compliant JSON-LD document

Variant: NM_004999.4(MYO6):c.2751dup (p.Gln918fs)

CA3897446

523937 (ClinVar)

Gene: MYO6
Condition: nonsyndromic genetic deafness
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 2f4065a0-5a55-4590-a672-f3b6bbcc2ed5
Approved on: 2023-07-25
Published on: 2023-10-05

HGVS expressions

NM_004999.4:c.2751dup
NM_004999.4(MYO6):c.2751dup (p.Gln918fs)
NC_000006.12:g.75890149dup
CM000668.2:g.75890149dup
NC_000006.11:g.76599866dup
CM000668.1:g.76599866dup
NC_000006.10:g.76656586dup
NG_009934.1:g.145958dup
NG_009934.2:g.145957dup
ENST00000369975.6:c.2751dup
ENST00000369977.8:c.2751dup
ENST00000369985.9:c.2751dup
ENST00000627432.3:c.2760dup
ENST00000653917.1:c.*858dup
ENST00000662184.1:c.*858dup
ENST00000662603.1:c.2751dup
ENST00000663400.1:c.*776dup
ENST00000664209.1:c.2751dup
ENST00000664640.1:c.2751dup
ENST00000671923.1:c.*858dup
ENST00000672093.1:c.2751dup
ENST00000369975.5:c.2751dup
ENST00000369977.7:c.2751dup
ENST00000369981.7:c.2751dup
ENST00000369985.8:c.2751dup
ENST00000615563.4:c.2751dup
ENST00000627432.2:c.2751dup
NM_001300899.1:c.2751dup
NM_004999.3:c.2751dup
NM_001300899.2:c.2751dup
NM_001368136.1:c.2751dup
NM_001368137.1:c.2751dup
NM_001368138.1:c.2736dup
NM_001368865.1:c.2751dup
NM_001368866.1:c.2751dup
NR_160538.1:n.3076dup

Likely Pathogenic

Met criteria codes 1
PVS1
Not Met criteria codes 13
PM6 PM2 PM1 PM4 PM5 BS4 BS1 BP3 PS2 PS4 PS1 PP1 BA1

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 c.2751dup (p.Gln918fs) frameshift variant in MYO6 is predicted to cause a premature stop codon in biologically-relevant exon 26 of 35 total exons, leading to a truncated or absent protein in a gene where loss of function is an established mechanism of autosomal dominant hearing loss (PVS1; PMID: 30192042). The highest minor allele frequency in gnomAD v.2.1.1 was 0.048% (52/109484) of European (non-Finnish) population, but was noted to occur in a low complexity region where variant quality was dubious, so BS1 was not applied. It was observed in 2 probands with moderate sensorineural hearing loss, meeting PS4_Supporting (PMID: 25080041, 33297549). In summary, this variant is likely pathogenic for autosomal dominant nonsyndromic hearing loss based on the ACMG/AMP criteria applied as specified by the ClinGen Hearing Loss Expert Panel: PVS1, PS4_Supporting (ClinGen Hearing Loss VCEP specifications version 2; 7/25/2023).
Met criteria codes
PVS1
Occurs in exon 26/35, leading to a truncated protein in a gene where loss of function is an established mechanism of disease. This exon is present in 7/8 transcripts in GTEx and is biologically expressed.
Not Met criteria codes
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM2
gnomAD v.2.1.1 MAF: 0.048% (52/109484) of European (non-Finnish) population
PM1
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
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
gnomAD v.2.1.1 MAF: 0.048% (52/109484) of European (non-Finnish) population, but was noted to occur in a low complexity region where variant quality was dubious, so BS1 was not applied. FAF (95% CI): 0.04140% (75/208794) European (non-Finnish) population.
BP3
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
PS4
Observed in 2 probands with moderate sensorineural hearing loss. PS4_Supporting was applied for this variant despite its higher than expected frequency in the general population to resolve the conflicting evidence (PMID: 25080041, 33297549). It was also observed homozygous in 2 Emirati individuals with HL (PMID: 36056583).
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
gnomAD v.2.1.1 MAF: 0.048% (52/109484) of European (non-Finnish) population
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