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

dbSNP: rs551348450

Total submissions: 8

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	RCV003403441	SCV004105168	uncertain significance	MYO6-related condition	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% (https://gnomad.broadinstitute.org/variant/6-76599857-G-GA). 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.
University of Washington Center for Mendelian Genomics, University of Washington	RCV001543426	SCV001761987	uncertain significance	Essential tremor		no assertion criteria provided	research