Submissions for variant NM_000256.3(MYBPC3):c.3713T>C (p.Leu1238Pro)

dbSNP: rs730880702

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158461	SCV000208396	likely pathogenic	not provided	2017-02-13	criteria provided, single submitter	clinical testing	The L1238P variant in the MYBPC3 gene has been reported in two probands with HCM (Choi et al., 2010; Berge et al., 2014). The variant segregated with HCM in 5 relatives of one affected proband (Choi et al., 2010). The L1238P variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The L1238P variant is a semiconservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function.
Invitae	RCV000459464	SCV000546430	likely pathogenic	Hypertrophic cardiomyopathy	2024-01-19	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 1238 of the MYBPC3 protein (p.Leu1238Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 20641121, 24111713, 27532257, 32841044, 35653365; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 181136). 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. Studies have shown that this missense change alters MYBPC3 gene expression (PMID: 32841044). 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.
3billion	RCV001808429	SCV002058124	likely pathogenic	Hypertrophic cardiomyopathy 4	2022-01-03	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000181136, PMID:20641121, PS1_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.96, 3CNET: 0.996, PP3_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M).Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Ambry Genetics	RCV003372628	SCV004081784	likely pathogenic	Cardiovascular phenotype	2023-08-22	criteria provided, single submitter	clinical testing	The p.L1238P variant (also known as c.3713T>C), located in coding exon 33 of the MYBPC3 gene, results from a T to C substitution at nucleotide position 3713. The leucine at codon 1238 is replaced by proline, an amino acid with similar properties. This alteration has been reported in subjects with hypertrophic cardiomyopathy (HCM) and has been noted to segregate with disease (Choi JO et al. Clin Cardiol, 2010 Jul;33:430-8; Berge KE et al. Clin Genet, 2014 Oct;86:355-60; Walsh R et al. Genet Med, 2017 Feb;19:192-203; Wright CF et al. Am J Hum Genet, 2019 Feb;104:275-286; external communication). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000158461	SCV000924852	likely pathogenic	not provided	2017-01-26	no assertion criteria provided	provider interpretation	Testing was performed at GeneDx. Given the moderate case data, segregation at least 4 individuals in one family, and absence in population databases, we consider this variant likely disease causing and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Pursuing additional segregation studies in other affected family members could strengthen the segregation data for this variant. The variant has been seen in at least 4 unrelated individuals with HCM (not including this patient's family). There is mild segregation data from the one family reported in the literature. A different genetic testing laboratory noted that they have seen this variant in one individual with HCM. Choi et al. 2010 report a Korean family in which 4 individuals with HCM carry this variant. Below is a pedigree for reference. Of note, the paper does not indicate how these patients were tested for genetic variants and do not list which genes were included in the original genetic testing. II-3 was 63yo at last follow up had an IVSd measuring 2.9cm, had NSVT on Holter and has an ICD. He had an EF of 70% and MRI showed areas of delayed enhancement. III-2 has HCM dx at age 40 with an IVSd 2.3cm, EF of 30%, apical thrombus, LAE, and afib. She also had hypertension. III-3 has HCM dx at age 27 with history of afib and VT, IVSd measuring 2.4cm and EF of 25%. Authors note he progressed to heart failure and DCM-like phenotype. He died of intractable VT at age 54. III-5 has HCM dx at age 28 with improved EF on follow up. IVSd of 1.7cm, NSVT on Holter and EF of 39%. Authors note he was a heavy alcoholic and developed a DCM phenotype at age 31. Once he gave up alcohol his EF and LVEDD returned to normal. Berge et al (2014) reports this variant in a Norwegian proband with HCM. No specific phenotypic information is included. Genetic testing was done on a research basis and not at a known laboratory, to our knowledge. Walsh et al (2016), in collaboration with Cook, Ware, and MacArthur, report that is variant was identified in an individual with HCM. Testing was performed at Oxford Medical Genetics Laboratories. No other details are provided. The variant is not present in the SHaRe database. There is no variation at codon 1238 listed in the Exome Aggregation Consortium Dataset (ExAC; http://exac.broadinstitute.org/), which currently includes variant calls on >60,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. The average coverage at that site in ExAC is 70x. There is no variation at codon 1238 listed in the Genome Aggregation Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. The average coverage at that site in gnomAD is 80x for exomes and 35x for genomes.