ClinVar Miner

Submissions for variant NM_002471.4(MYH6):c.1763A>C (p.Asp588Ala) (rs142992009)

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Total submissions: 12
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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 RCV000172566 SCV000051407 likely benign not provided 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000151221 SCV000199079 uncertain significance not specified 2013-08-02 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The Asp588Ala varia nt in MYH6 is present in 0.2% (19/8600) of European American chromosomes by the NHLBI Exome Sequencing Project (; dbSNP rs142992 009). It has also been reported in 1 individual with CHD (Granados-Riveron 2010) . Computational analyses (biochemical amino acid properties, conservation, Align GVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impac t to the protein. The variant?s population frequency suggests that it is more li kely benign but is too low to confidently rule out a disease-causing role. Addit ional information is needed to fully assess its clinical significance.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000151221 SCV000226269 likely benign not specified 2015-06-05 criteria provided, single submitter clinical testing
Invitae RCV000989183 SCV000287397 likely benign Familial hypertrophic cardiomyopathy 14 2019-12-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000249428 SCV000318269 uncertain significance Inborn genetic diseases 2014-06-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: UNCERTAIN: Alteration(s) of Uncertain Clinical Significance Detected
GeneDx RCV000151221 SCV000513788 likely benign not specified 2017-12-07 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Integrated Genetics/Laboratory Corporation of America RCV000172566 SCV000697923 likely benign not provided 2016-02-15 criteria provided, single submitter clinical testing Variant summary: The variant of interest affects a conserved nucleotide and results in a replacement of a medium size and acidic Aspartic acid (D) with a small size and hydrophobic Alanine (A). 2/4 in silico tools predict the variant to be neutral. It was found in the large and board cohorts of the ExAC project, predominantly in the European subpopulation at an allele frequency of 0.0033 which exceeds the maximal expected allele frequency of a disease causing MYH6 allele (0.000025) indicating the variant to be benign. The variant was found in one HCM patient however, without strong evidence for pathogenicity (Lopes_Heart_2015). It was also detected in a patient with hypoplastic left heart syndrome in compound heterozygosity with c.3619 G>A, p.E1207K (Theis et al, 2015). The proband inherited the variant of interest from her healthy mother and the variant was also found in her healthy sister further supporting a non HCM causing impact of the variant. However authors hypothesize that MYH6 demonstrated recessive pattern of inheritance. Most clinical laboratories classify variant as Benign/likely Benign, however at least one reputable lab classified the variant as VUS. Considering all evidence, the variant is a normal variant for HCM but the possibility of the variant to result in autosomal recessive hypoplastic left heart syndrome cannot be excluded therefore, it was classified as Likely Benign.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000151221 SCV000740615 likely benign not specified 2016-09-08 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000172566 SCV000884187 likely benign not provided 2017-11-10 criteria provided, single submitter clinical testing The p.Asp588Ala variant (rs142992009) has been reported in individuals not selected for arrhythmia, cardiomyopathy, or a family history of sudden death (Ng, 2013). In addition, this variant has been observed in cases associated with sudden infant death syndrome, hypoplastic left heart, and hypertrophic cardiomyopthy; however without segregation with disease (Neubauer, 2017; Theis, 2015; Lopes, 2013). This variant is listed in the Genome Aggregation Database (gnomAD) with an overall population frequency of 0.2 percent (identified on 488 out of 277,218 chromosomes) and has been reported to the ClinVar database (Variation ID: 155811). Given the overabundance in the healthy population and control patients, this variant is likely to be benign.
Mendelics RCV000989183 SCV001139405 benign Familial hypertrophic cardiomyopathy 14 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000172566 SCV001149146 likely benign not provided 2017-05-01 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000143919 SCV000188793 benign Primary familial hypertrophic cardiomyopathy 2014-12-05 no assertion criteria provided clinical testing

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