ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.2602G>A (p.Gly868Ser)

dbSNP: rs775890771
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000618486 SCV000735781 uncertain significance Cardiovascular phenotype 2022-03-07 criteria provided, single submitter clinical testing The p.G868S variant (also known as c.2602G>A), located in coding exon 25 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 2602.This alteration changes the glycine at codon 868 to serine, an amino acid with similar properties. This alteration was observed in a reportedly healthy control cohort in a study of hypertrophic cardiomyopathy genetic testing, and has also been detected in a left ventricular non-compaction cardiomyopathy cohort and a Wolff-Parkinson-White cohort; however details were limited (Kapplinger JD et al. J Cardiovasc Transl Res, 2014 Apr;7:347-61; Richard P et al. Clin. Genet., 2019 Mar;95:356-367; Coban-Akdemir ZH et al. Am J Med Genet A, 2020 06;182:1387-1399). In a minigene assay, this alteration resulted in some aberrant splicing, as did the reference to a lesser degree; however, the physiologic relevance of these data are unclear (Ito K et al. Proc. Natl. Acad. Sci. U.S.A., 2017 07;114:7689-7694). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. The amino acid position is not well conserved in available vertebrate species, and the missense change is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001174770 SCV001338092 uncertain significance not specified 2020-01-20 criteria provided, single submitter clinical testing Variant summary: MYBPC3 c.2602G>A (p.Gly868Ser) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5' splicing donor site. Four predict the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 6.1e-05 in 227862 control chromosomes (gnomAD, exomes only). This frequency is not significantly higher than expected for a pathogenic variant in MYBPC3 causing Cardiomyopathy (6.1e-05 vs 0.001), allowing no conclusion about variant significance. c.2602G>A has been reported in the literature in a healthy individual (Kapplinger_2014). This report does not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health RCV001182931 SCV001348533 uncertain significance Cardiomyopathy 2023-06-29 criteria provided, single submitter clinical testing This missense variant replaces glycine with serine at codon 868 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). However, this variant causes a G>A nucleotide substitution at the last nucleotide of exon 25 of the MYBPC3 gene, and splice site prediction tools suggest that this variant may impact RNA splicing. An experimental mini-gene splicing assay has shown that this variant may cause partially aberrant splicing (PMID: 28679633); the clinical relevance of this observation is not known. This variant has been reported in an individual affected with dilated cardiomyopathy who also carried a pathogenic truncation variant in the TTN gene that could explain the observed phenotype (PMID: 32826072). This variant has also been reported in an individual affected with Wolff-Parkinson-White syndrome, supraventricular tachycardia, and Ebstein anomaly (PMID: 32233023) and in an individual affected with left ventricular noncompaction (PMID: 30471092). This variant has been identified in 14/227862 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Invitae RCV001206577 SCV001377891 uncertain significance Hypertrophic cardiomyopathy 2022-10-31 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 868 of the MYBPC3 protein (p.Gly868Ser). This variant also falls at the last nucleotide of exon 25, which is part of the consensus splice site for this exon. This variant is present in population databases (rs775890771, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of left ventricular noncompaction (PMID: 34088380). ClinVar contains an entry for this variant (Variation ID: 518630). 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 tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV001182931 SCV002042173 uncertain significance Cardiomyopathy 2019-07-05 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002476376 SCV002775099 uncertain significance Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10 2022-04-11 criteria provided, single submitter clinical testing

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