Submissions for variant NM_000256.3(MYBPC3):c.2783C>T (p.Ser928Leu)

gnomAD frequency: 0.00004  dbSNP: rs773819168

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Human Genetics, University of Leuven	RCV000498962	SCV000579549	uncertain significance	Prolonged QT interval	2017-04-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000498497	SCV000589344	uncertain significance	not provided	2022-09-21	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24111713, 22857948, 25214167, 33782553, 29853478, 31323898, 32369506, 16335287, 30847666)
Invitae	RCV000799722	SCV000939398	uncertain significance	Hypertrophic cardiomyopathy	2022-08-23	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 928 of the MYBPC3 protein (p.Ser928Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 16335287, 22857948, 24111713, 33782553; Invitae). ClinVar contains an entry for this variant (Variation ID: 427958). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). 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.
Illumina Laboratory Services, Illumina	RCV001104920	SCV001261826	uncertain significance	Left ventricular noncompaction 10	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001104921	SCV001261827	uncertain significance	Hypertrophic cardiomyopathy 4	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Color Diagnostics, LLC DBA Color Health	RCV001179576	SCV001344270	uncertain significance	Cardiomyopathy	2023-03-16	criteria provided, single submitter	clinical testing	This missense variant replaces serine with leucine at codon 928 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 24111713, 22857948, 31323898). One of these individuals also carried a pathogenic variant in the MYH7 gene that could explain the observed phenotype (PMID: 22857948). This variant has been identified in 6/247572 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193932	SCV001363109	uncertain significance	not specified	2019-02-12	criteria provided, single submitter	clinical testing	Variant summary: MYBPC3 c.2783C>T (p.Ser928Leu) results in a non-conservative amino acid change located in the Fibronectin type III domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.5e-05 in 244814 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2783C>T has been reported in the literature in affected individuals (Berge_2014, Brito_2012, Brito_2005). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. Co-occurrences with other pathogenic variants have been reported (MYBPC3 c.2373dupG, p.W792VfsX41; MYH7 c.788T>C, p.Ile263Thr) (Berge_2014, Brito_2012). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Ambry Genetics	RCV002438198	SCV002748256	uncertain significance	Cardiovascular phenotype	2023-04-18	criteria provided, single submitter	clinical testing	The p.S928L variant (also known as c.2783C>T), located in coding exon 27 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 2783. The serine at codon 928 is replaced by leucine, an amino acid with dissimilar properties. This variant has been detected in hypertrophic cardiomyopathy (HCM) cohorts and individuals with HCM; however, it co-occurred with pathogenic mutations in cardiomyopathy-related genes in at least two cases, and cohort reports may overlap (Brito D et al. Rev Port Cardiol, 2005 Sep;24:1137-46; Brito D et al. Rev Port Cardiol, 2012 Sep;31:577-87; Berge KE et al. Clin. Genet., 2014 Oct;86:355-60; Nijenkamp LLAM et al. Circ Heart Fail. 2018 06;11(6):e004133; Helms AS et al. Circ Genom Precis Med. 2020 Oct;13(5):396-405; Harper AR et al. Nat Genet. 2021 Feb;53(2):135-142). This variant has also been detected in an individual reported to have long QT syndrome, and in an individual who underwent genetic testing for dilated cardiomyopathy; however, clinical details were limited (Robyns T et al. Eur. J. Hum. Genet. 2017 12;25(12):1313-1323; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002481558	SCV002791300	uncertain significance	Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10	2021-10-11	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV000498497	SCV001920330	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000498497	SCV001931459	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000498497	SCV001957873	uncertain significance	not provided		no assertion criteria provided	clinical testing