Submissions for variant NM_000256.3(MYBPC3):c.596T>C (p.Leu199Pro)

gnomAD frequency: 0.00002  dbSNP: rs878853835

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000231638	SCV000284247	uncertain significance	Hypertrophic cardiomyopathy	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 199 of the MYBPC3 protein (p.Leu199Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 30762279, 32009526). ClinVar contains an entry for this variant (Variation ID: 237430). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.
GeneDx	RCV001568979	SCV001792946	uncertain significance	not provided	2019-12-18	criteria provided, single submitter	clinical testing	Published in an individual with DCM, who also harbored a variant in the SOS1 gene (Aljeaid et al., 2019); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID# 237430; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 30762279)
Ambry Genetics	RCV003165597	SCV003857396	uncertain significance	Cardiovascular phenotype	2022-12-13	criteria provided, single submitter	clinical testing	The p.L199P variant (also known as c.596T>C), located in coding exon 5 of the MYBPC3 gene, results from a T to C substitution at nucleotide position 596. The leucine at codon 199 is replaced by proline, an amino acid with similar properties. This variant co-occurred with variants in the SOS1 and MAP2K2 genes in an individual with dilated cardiomyopathy (Aljeaid D et al. Am J Med Genet A, 2019 Apr;179:608-614). This variant has also been detected in a hypertrophic cardiomyopathy cohort (Harper AR et al. Nat Genet, 2021 Feb;53:135-142). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786617	SCV005398424	uncertain significance	Hypertrophic cardiomyopathy 4	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hypertrophic cardiomyopathy 4 (HCM; MIM#115197). (I) 0108 - This gene is associated with both recessive and dominant disease. Dominant inheritance is frequently reported in adult onset conditions, however recessive inheritance results in a more severe early onset phenotype (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 32841044). (I) 0200 - Variant is predicted to result in a missense amino acid change from leucine to proline. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated Ig-like C2-type 1 domain (UniProt). (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. This alternative change (p.(Leu199Arg)) has been reported as a VUS and observed in an individual with dilated cardiomyopathy (DCM) (LOVD, PMID: 27532257). (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported as a VUS. It has been observed in a cohort with HCM, in another individual with cardiomyopathy and an additional VUS in the LMNA gene, and a third individual wth DCM and additional VUS in the SOS1 and MAP2K2 genes. In this latter individual, this variant was regarded as likely disease causing (ClinVar, PMID: 33495597, PMID: 30762279, PMID: 32009526). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign