Submissions for variant NM_004999.4(MYO6):c.826C>T (p.Arg276Ter)

gnomAD frequency: 0.00002  dbSNP: rs727503326

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000151469	SCV000199516	pathogenic	Rare genetic deafness	2014-01-27	criteria provided, single submitter	clinical testing	The Arg276X variant in MYO6 has not been previously reported in individuals with hearing loss or in large population studies. This variant introduces a prematur e stop codon at position 276 leading to either a truncated or absent protein. I n summary, this variant meets our criteria for pathogenicity (http://pcpgm.partn ers.org/LMM).
Eurofins Ntd Llc (ga)	RCV000599449	SCV000708497	pathogenic	not provided	2017-05-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000599449	SCV000709820	uncertain significance	not provided	2020-12-21	criteria provided, single submitter	clinical testing	Nonsense 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; Identified in patients with hearing loss referred for genetic testing at GeneDx and in published literature (Sloan-Heggen et al., 2016); This variant is associated with the following publications: (PMID: 29044474, 26969326, 31589614)
Fulgent Genetics, Fulgent Genetics	RCV000763565	SCV000894396	pathogenic	Autosomal dominant nonsyndromic hearing loss 22; Autosomal recessive nonsyndromic hearing loss 37	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000599449	SCV002228138	pathogenic	not provided	2024-02-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg276*) 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). This variant is present in population databases (rs727503326, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with deafness (PMID: 26969326). ClinVar contains an entry for this variant (Variation ID: 164634). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
AiLife Diagnostics, AiLife Diagnostics	RCV000599449	SCV002502565	likely pathogenic	not provided	2022-01-05	criteria provided, single submitter	clinical testing
3billion, Medical Genetics	RCV002250575	SCV002521636	pathogenic	Autosomal recessive nonsyndromic hearing loss 37	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000164634 / PMID: 26969326). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Ambry Genetics	RCV004019820	SCV004953976	pathogenic	Inborn genetic diseases	2023-11-21	criteria provided, single submitter	clinical testing	The c.826C>T (p.R276*) alteration, located in exon 10 (coding exon 9) of the MYO6 gene, consists of a C to T substitution at nucleotide position 826. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 276. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of 0.002% (4/251012) total alleles studied. The highest observed frequency was 0.009% (3/34560) of Latino alleles. This variant has been reported in one individual with a personal and family history of hearing loss (Wu, 2022). Based on the available evidence, this alteration is classified as pathogenic.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV001753534	SCV001994794	pathogenic	Autosomal dominant nonsyndromic hearing loss 22	2021-10-27	no assertion criteria provided	clinical testing