ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.3413G>C (p.Arg1138Pro)

dbSNP: rs187705120
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000035587 SCV000059238 uncertain significance not specified 2013-02-11 criteria provided, single submitter clinical testing The Arg1138Pro variant in MYBPC3 has not been reported in the literature nor pre viously identified by our laboratory. The frequency of this variant in large Eur opean American and African American populations cannot be determined from the NH LBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/) because coverag e at this position was insufficient or unavailable. Computational analyses (bioc hemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) sug gest that this variant may impact the protein, though this information is not pr edictive enough to determine pathogenicity. At this time, additional information is needed to fully assess the clinical significance of this variant.
GeneDx RCV000589004 SCV000208171 uncertain significance not provided 2020-05-13 criteria provided, single submitter clinical testing Reported variant in the literature in individuals referred for cardiomyopathy testing, but clinical and segregation data are limited or absent (Coppini et al., 2014; Ito et al., 2017; Walsh et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 25524337, 28679633, 27532257, 33297573)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000589004 SCV000696329 uncertain significance not provided 2017-03-31 criteria provided, single submitter clinical testing Variant summary: The MYBPC3 c.3413G>C (p.Arg1138Pro) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant is absent in 80556 control chromosomes and has been reported in the literature in at least one patient with HCM without strong evidence for causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, until additional evidence becomes available, this variant is classified as VUS.
Blueprint Genetics RCV000589004 SCV000928089 uncertain significance not provided 2018-11-30 criteria provided, single submitter clinical testing
Invitae RCV001059373 SCV001223997 likely pathogenic Hypertrophic cardiomyopathy 2023-12-14 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 1138 of the MYBPC3 protein (p.Arg1138Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 25524337, 27532257, 28679633; Invitae). ClinVar contains an entry for this variant (Variation ID: 42712). 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 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.
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV001198124 SCV001368955 uncertain significance Hypertrophic cardiomyopathy 4 2019-03-29 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PP3.
Baylor Genetics RCV003333006 SCV004040884 likely pathogenic Left ventricular noncompaction 10 2023-03-28 criteria provided, single submitter clinical testing
Baylor Genetics RCV001198124 SCV004040941 likely pathogenic Hypertrophic cardiomyopathy 4 2023-03-28 criteria provided, single submitter clinical testing
Ambry Genetics RCV004018758 SCV004938649 uncertain significance Cardiovascular phenotype 2022-02-03 criteria provided, single submitter clinical testing The c.3413G>C (p.R1138P) alteration is located in exon 31 (coding exon 31) of the MYBPC3 gene. This alteration results from a G to C substitution at nucleotide position 3413, causing the arginine (R) at amino acid position 1138 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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