ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.3713T>C (p.Leu1238Pro) (rs730880702)

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Total submissions: 3
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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 2018-09-10 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 1238 of the MYBPC3 protein (p.Leu1238Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 24111713, 27532257, Invitae) and has been reported to segregate with disease in a single family (PMID: 20641121). ClinVar contains an entry for this variant (Variation ID: 181136). 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 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.
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.

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