ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.1633C>A (p.Leu545Met) (rs377163678)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000151120 SCV000198890 uncertain significance not specified 2013-12-05 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The Leu545Met varia nt in MYBPC3 has been reported in 1 individual with HCM, but it was also present in 1% (2/200) control chromosomes (Van Dreist 2004). It has also been identifie d in 1/4172 African American chromosomes by the NHLBI Exome Sequencing Project (; dbSNP rs377163678). Computational analyses (b iochemical amino acid properties, conservation, PolyPhen2, and SIFT) suggest tha t this variant may impact the normal function of the protein, though this inform ation is not conclusively predictive. Additional information is needed to fully assess the clinical significance of the Leu545Met variant.
GeneDx RCV000766337 SCV000208042 uncertain significance not provided 2018-03-22 criteria provided, single submitter clinical testing The L545M variant has been reported in a cohort of 389 patients with HCM, but was also observed in 1% of control alleles (Van Driest et al., 2004). Nevertheless, the L545M variant was not observed with any significant frequency in approximately 6,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Additionally, L545M has been seen in two individuals referred for cardiomyopathy testing at GeneDx and is classified in ClinVar by another clinical laboratory as a variant of uncertain significance in association with cardiomyopathy (ClinVar SCV000198890.3; Landrum et al., 2016). Although the L545M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, this substitution occurs at a position that is conserved across species. Consequently, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Ambry Genetics RCV000621152 SCV000735940 uncertain significance Cardiovascular phenotype 2017-07-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000686894 SCV000814435 uncertain significance Hypertrophic cardiomyopathy 2018-02-28 criteria provided, single submitter clinical testing This sequence change replaces leucine with methionine at codon 545 of the MYBPC3 protein (p.Leu545Met). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and methionine. This variant is present in population databases (rs377163678, ExAC 0.04%). This variant has been reported in an individual affected with hypertrophic cardiomyopathy, as well as in 2/200 (1%) control samples (PMID: 15519027). ClinVar contains an entry for this variant (Variation ID: 164105). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.

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