ClinVar Miner

Submissions for variant NM_004999.4(MYO6):c.737A>G (p.His246Arg)

dbSNP: rs121912560
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Total submissions: 4
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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 RCV000219073 SCV000271246 likely pathogenic Rare genetic deafness 2015-07-30 criteria provided, single submitter clinical testing The p.His246Arg variant in MYO6 has been reported in one individual with progres sive, post-lingual sensorineural hearing loss and left ventricular hypertrophy ( LVH), and it segregated with hearing loss in 9 affected relatives (Mohiddin 2004 ). Two family members (ages 12 and 28 years) carried the variant but did not hav e hearing loss, which may reflect reduced penetrance or variable onset. Alternat ively, of the 11 family members that carried the p.His246Arg variant, only 4 ind ividuals presented with cardiac hypertrophy, while another 3 family members were reported to have an abnormal ECG. While this could also indicate reduced penetr ance of LVH, given that no other variant in the MYO6 gene has been associated wi th cardiac hypertrophy, it is possible that the LVH in the family is caused by a n unrelated etiology. Of note, one family member who did not carry the variant a nd did not have sensorineural hearing loss was reported to have LVH which indica tes that this MYO6 variant does not segregate with that manifestation; however, the authors attributed this individual's cardiac features to valvar and ischaemi c disease. The variant was absent in population databases. In summary, although additional studies are required to fully establish its clinical significance, th is variant is likely pathogenic.
GeneDx RCV001582473 SCV001813096 likely pathogenic not provided 2023-05-01 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15060111, 18212818, 18348273, 29044474, 29224747, 27535533, 34662886)
Invitae RCV001582473 SCV003017778 pathogenic not provided 2024-01-03 criteria provided, single submitter clinical testing This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 246 of the MYO6 protein (p.His246Arg). This variant is present in population databases (rs121912560, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal dominant deafness (PMID: 15060111). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8581). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYO6 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000009112 SCV000029329 pathogenic Sensorineural deafness with hypertrophic cardiomyopathy 2004-04-01 no assertion criteria provided literature only

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