ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.1828G>C (p.Asp610His) (rs371564200)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000210552 SCV000262974 likely pathogenic Inborn genetic diseases 2013-08-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Insufficient or conflicting evidence,Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
GeneDx RCV000482228 SCV000565276 likely pathogenic not provided 2015-07-31 criteria provided, single submitter clinical testing The D610H likely pathogenic variant in the MYBPC3 gene has been reported previously in association with HCM and sudden infant death syndrome (SIDS) (Olivotto I et al., 2008; Millat G et al., 2010; Brion M et al., 2010). Initially, D610H was reported in one individual with HCM (Olivotto et al., 2008). Subsequently, Millat et al. (2010) reported the D610H variant in one individual with HCM who also harbors the TNNT2 R278C variant. In addition, D610H was reported in one case of SIDS, a 24-week-old male with an inconclusive autopsy (Brion et al., 2012). One other clinical laboratory classifies D610H as a variant of unknown significance and detected D610H in two individuals with HCM, one of whom also carried a second variant of unknown significance (Landrum M et al., 2014). Additionally, the D610H variant has been observed in one other unrelated individual with HCM referred for testing at GeneDx. Considering all publications, D610H in the MYBPC3 gene was absent from 700 control alleles (Olivotto et al., 2008; Millat et al., 2010). Furthermore, the D610H variant was not observed in approximately 6,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.
Invitae RCV000477331 SCV000546418 likely pathogenic Hypertrophic cardiomyopathy 2018-03-30 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with histidine at codon 610 of the MYBPC3 protein (p.Asp610His). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and histidine. This variant is present in population databases (rs371564200, ExAC 0.04%). This variant has been reported in individual affected with hypertrophic cardiomyopathy and in a case of sudden infant death syndrome (SIDS) (PMID: 18533079, 28356264, 20624503, 22361390, 25740977, 28074886). ClinVar contains an entry for this variant (Variation ID: 42576). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. A different missense substitution at this codon (p.Asp610Asn) has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 22857948). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035443 SCV000059091 uncertain significance not specified 2018-03-07 criteria provided, single submitter clinical testing The p.Asp610His variant in MYBPC3 has been detected in 8 individuals with HCM (O livotto 2008, Millat 2010, Brito 2012, Rafael 2017 and LMM unpublished data) and one child who died from sudden infant death syndrome (SIDS; Brion 2012). Two of these individuals carried additional pathogenic variants and one individual was homozygous for the p.Asp610His variant (Rafael 2017, LMM data). In one family, this variant segregated with disease in 2 affected relatives, but was not presen t in an additional affected relative, raising the possibility that it may not be disease causing. The variant has also been identified in multiple older individ uals without disease. This variant has also been reported in ClinVar (Variation ID: 42576). This variant has also been identified in 6/113666 European chromosom es by the Genome Aggregation Database (gnomAD,; dbSNP rs371564200). Computational prediction tools suggest that the p.Asp610His variant may impact the protein, though this information is not predictive enoug h to determine pathogenicity. In summary, the clinical significance of the p.Asp 610His variant is uncertain. ACMG/AMP Criteria applied: PP3; PS4_Supporting; BP2 .
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000622855 SCV000740355 uncertain significance Primary familial hypertrophic cardiomyopathy 2016-07-26 criteria provided, single submitter clinical testing

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