ClinVar Miner

Submissions for variant NM_004999.4(MYO6):c.2751dup (p.Gln918fs)

dbSNP: rs551348450
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel RCV002250426 SCV002520697 likely pathogenic Nonsyndromic genetic hearing loss 2023-07-25 reviewed by expert panel curation 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).
GeneDx RCV000627419 SCV000748415 pathogenic not provided 2022-11-09 criteria provided, single submitter clinical testing Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33297549, 30245029, 25080041)
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000627419 SCV001905664 pathogenic not provided 2021-09-15 criteria provided, single submitter clinical testing
Mendelics RCV002248831 SCV002518342 uncertain significance not specified 2022-05-04 criteria provided, single submitter clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV003336098 SCV004046004 likely pathogenic Autosomal dominant nonsyndromic hearing loss 22 criteria provided, single submitter clinical testing This frameshifting variant in exon 26 of 35 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a heterozygous variant in one individual with late-onset progressive, moderate non-syndromic hearing loss (PMID: 25080041). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.032% (76/235680). Based on the available evidence, the c.2751dup (p.Gln918ThrfsTer24) variant is classified as Likely Pathogenic.
PreventionGenetics, part of Exact Sciences RCV004527692 SCV004105168 uncertain significance MYO6-related disorder 2023-08-04 criteria provided, single submitter clinical testing The MYO6 c.2751dupA variant is predicted to result in a frameshift and premature protein termination (p.Gln918Thrfs*24). This variant has been reported in the gnomAD public population database at a subpopulation frequency as high as 0.047% ( However, the c.2751dup variant is part of a mononucleotide repeat of nine adenosines, which makes this allele frequency estimate unreliable. This variant has previously been reported as causative in a family with autosomal dominant, progressive, mild to moderate nonsyndromic hearing loss with onset in the fifth decade (Kwon et al. 2014. PubMed ID: 25080041). Despite this family having five affected individuals across two generations, the c.2751dup variant was only reported as being present in one individual with unclear genotype of the other affected and unaffected family members. This variant has also been reported in the heterozygous state in two related patients with autosomal dominant hearing loss, although a potentially causative variant in another gene was also identified (García-García et al 2020. PubMed ID: 33297549). This variant has been detected at PreventionGenetics in two unrelated families; the first with the c.2751dup variant in the heterozygous state in two siblings with hearing loss, and the second with the c.2751dup variant in the homozygous state in a single affected individual with no family history of hearing loss. Frameshift variants in MYO6 are expected to be pathogenic. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Invitae RCV000627419 SCV004531993 pathogenic not provided 2023-10-10 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln918Thrfs*24) in the MYO6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYO6 are known to be pathogenic (PMID: 12687499, 18348273, 23767834, 25999546, 30582396). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with autosomal dominant non-syndromic hearing loss (PMID: 25080041). ClinVar contains an entry for this variant (Variation ID: 523937). For these reasons, this variant has been classified as Pathogenic.
Molecular Genetics, Royal Melbourne Hospital RCV002250426 SCV004812588 pathogenic Nonsyndromic genetic hearing loss 2022-03-03 criteria provided, single submitter clinical testing This sequence change in MYO6 is a frameshift variant predicted to cause a premature stop codon, p.(Gln918Thrfs*24) in biologically-relevant-exon 26/35 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (ClinGen). The highest population minor allele frequency in gnomAD v3.1 is 0.007% (1/14,740 alleles) in the Latino/Admixed American population. The prevalence of the variant in individuals with non-syndromic hearing loss is significantly increased compared with the prevalence in controls (Odds ratio 17.2, 95% confidence interval: 1.79 - 165) (Cases: PMID: 25080041, 26969326, 33297549; Controls: gnomAD v3.1 Latino/Admixed American population). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PS4_Moderate.
University of Washington Center for Mendelian Genomics, University of Washington RCV001543426 SCV001761987 uncertain significance Essential tremor no assertion criteria provided research

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