ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.3569G>A (p.Arg1190His) (rs117354682)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766375 SCV000208395 uncertain significance not provided 2018-03-15 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the MYBPC3 gene. The R1190H variant has reported in one patient with LVNC (Miszalski-Jamka et al., 2017); however, functional studies and segregation analysis were not performed. The R1190H variant is observed 4/126532 (0.003%) alleles from individuals of European (non-Finnish) ancestry and in 5/23994 (0.02%) alleles from individuals of African ancestry in large population cohorts (Lek et al., 2016). The R1190H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Nevertheless, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect.
Ambry Genetics RCV000252750 SCV000318642 uncertain significance Cardiovascular phenotype 2013-05-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000527109 SCV000623598 uncertain significance Hypertrophic cardiomyopathy 2018-08-16 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 1190 of the MYBPC3 protein (p.Arg1190His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs117354682, ExAC 0.02%). This variant has not been reported in the literature in individuals with MYBPC3-related disease. ClinVar contains an entry for this variant (Variation ID: 42722). 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 and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035597 SCV000059248 uncertain significance not specified 2008-05-23 no assertion criteria provided clinical testing
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000766375 SCV000925159 uncertain significance not provided 2017-08-15 no assertion criteria provided provider interpretation MYBPC3, Exon 32, c.3569G>A (p.Arg1190His), heterozygous, Uncertain Significance Given the high frequency in gnomAD we consider this variant a variant of uncertain significance, probably benign and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Per the lab report this variant has not been reported in association with disease. However, there are multiple assertions in ClinVar, all as variant of uncertain significance (GeneDx, CHEO, LMM, Ambry). None of these entries provide case data. Per the lab report "Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT,, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have notconfirmed by published functional studies and their clinical significance is uncertain." The variant was reported online in 13 of 138479 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in multiple ancestral groups with the highest frequency in African individuals (MAF=0.02084%). The phenotype of those individuals is not publicly available.

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