ClinVar Miner

Submissions for variant NM_002471.4(MYH6):c.824T>A (p.Ile275Asn)

gnomAD frequency: 0.00019  dbSNP: rs201327273
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health RCV000171837 SCV000051000 uncertain significance Primary dilated cardiomyopathy 2018-04-05 criteria provided, single submitter research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000037541 SCV000061199 uncertain significance not specified 2012-04-20 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The Ile275Asn varia nt (MYH6) was reported in two individuals with DCM (Carniel 2005, Hershberger 20 10, Rampersaud 2011). One of these individuals also carried a pathogenic DCM va riant as well as a second variant in MYH6 (Arg1502Gln) (Hershberger 2010). In th e family reported by Carniel 2005, the variant was detected in multiple affected but also unaffected individuals. The variant was present in 0.05% (3/7020) of E uropean American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS/); however, this frequency is too l ow to confidently rule out a disease causing role. Isoleucine (Ile) at position 275 is not well conserved in evolution, suggesting that a change may be tolerate d. Other computational analyses (biochemical amino acid properties, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to t he protein. In summary, this variant is more likely to be benign but additional studies are needed to determine this with confidence.
Invitae RCV000989184 SCV000546148 likely benign Hypertrophic cardiomyopathy 14 2023-12-22 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute RCV000624229 SCV000740611 uncertain significance Primary familial dilated cardiomyopathy 2016-07-29 criteria provided, single submitter clinical testing
Mendelics RCV000989184 SCV001139406 uncertain significance Hypertrophic cardiomyopathy 14 2019-05-28 criteria provided, single submitter clinical testing
GeneDx RCV001572348 SCV001796973 uncertain significance not provided 2023-07-12 criteria provided, single submitter clinical testing Reported with the R1502Q variant in the MYH6 gene in two individuals with DCM; one individual also harbored a pathogenic variant in the TNNT2 gene (Hershberger et al., 2010; Rampersaud et al., 2011), and one individual harbored a third missense variant in the MYH6 gene (Carniel et al., 2005); Also reported in two individuals with HCM (Lopes et al., 2015), and one individual from the ClinSeq cohort of individuals who underwent exome sequencing but were not selected for a history of cardiomyopathy, arrhythmia or family history of sudden cardiac death (Ng et al., 2013); 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: 22337857, 23861362, 23299917, 20215591, 15998695, 21483645, 25351510, AlMutairi2020[Publication])
Ambry Genetics RCV002426562 SCV002681869 likely benign Cardiovascular phenotype 2022-12-21 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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