ClinVar Miner

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

gnomAD frequency: 0.00002  dbSNP: rs727503326
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Total submissions: 9
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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
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
Invitae RCV000599449 SCV002228138 pathogenic not provided 2022-11-26 criteria provided, single submitter clinical testing This variant is present in population databases (rs727503326, gnomAD 0.009%). 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 premature translational stop signal has been observed in individual(s) with deafness (PMID: 26969326). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 164634).
AiLife Diagnostics, AiLife Diagnostics RCV000599449 SCV002502565 likely pathogenic not provided 2022-01-05 criteria provided, single submitter clinical testing
3billion 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

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