ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.604A>C (p.Lys202Gln) (rs730880623)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000158297 SCV000208232 likely pathogenic not provided 2014-09-19 criteria provided, single submitter clinical testing p.Lys202Gln (AAG>CAG): c.604 A>C in exon 5 of the MYBPC3 gene (NM_000256.3). The Lys202Gln variant in the MYBPC3 gene has been reported as possibly disease-associated in one individual with idiopathic dilated cardiomyopathy, and was absent from 492 control chromosomes in this study (Hershberger R et al., 2010). Lys202Gln results in a semi-conservative amino acid substitution of a positively-charged Lysine with a neutral Glutamine at a position that is well conserved across species. In silico analysis predicts Lys202Gln is damaging to the protein structure/function. Mutations in nearby residues (Gln208His, Ser212Arg) have been reported in association with HCM, further supporting the functional importance of this region of the protein. Furthermore, Lys202Gln was not observed in approximately 6000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, Lys202Gln is a good candidate for a disease-causing mutation. Mutations in the MYBPC3 gene have been reported in 20%-30% of patients with autosomal dominant familial hypertrophic cardiomyopathy (HCM), and have been reported less frequently in patients with autosomal dominant familial dilated cardiomyopathy (DCM) (Cirino A et al., 2011; Hershberger R et al., 2009). The variant is found in HCM,DCM-CRDM panel(s).
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000203144 SCV000257656 uncertain significance Dilated cardiomyopathy 1A 2015-05-11 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000221441 SCV000271997 uncertain significance not specified 2016-01-13 criteria provided, single submitter clinical testing The p.Lys202Gln variant in MYBPC3 has been reported in 1 individual with DCM. Th is variant has also been identified in 5/62340 European chromosomes by the Exome Aggregation Consortium (ExAC,; dbSNP rs730880623 ). Computational prediction tools and conservation analysis suggest that the p.L ys202Gln variant may impact the protein, though this information is not predicti ve enough to determine pathogenicity. In summary, the clinical significance of t he p.Lys202Gln variant is uncertain.
Invitae RCV000536676 SCV000623616 uncertain significance Hypertrophic cardiomyopathy 2019-12-11 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamine at codon 202 of the MYBPC3 protein (p.Lys202Gln). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamine. This variant is present in population databases (rs730880623, ExAC 0.008%). This variant has been observed in an individual affected with dilated cardiomyopathy (PMID: 20215591). ClinVar contains an entry for this variant (Variation ID: 181046). 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.
Ambry Genetics RCV000621144 SCV000735602 uncertain significance Cardiovascular phenotype 2016-11-03 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV001182010 SCV001347320 uncertain significance Cardiomyopathy 2019-11-17 criteria provided, single submitter clinical testing

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