rs773819168
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3
The NM_000256.3(MYBPC3):c.2783C>T(p.Ser928Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000552 in 1,612,436 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S928S) has been classified as Likely benign.
Frequency
Consequence
NM_000256.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYBPC3 | NM_000256.3 | c.2783C>T | p.Ser928Leu | missense_variant | 27/35 | ENST00000545968.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.2783C>T | p.Ser928Leu | missense_variant | 27/35 | 5 | NM_000256.3 | P4 | |
MYBPC3 | ENST00000399249.6 | c.2783C>T | p.Ser928Leu | missense_variant | 26/34 | 5 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152204Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000242 AC: 6AN: 247572Hom.: 0 AF XY: 0.0000223 AC XY: 3AN XY: 134426
GnomAD4 exome AF: 0.0000575 AC: 84AN: 1460232Hom.: 0 Cov.: 31 AF XY: 0.0000578 AC XY: 42AN XY: 726358
GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152204Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74346
ClinVar
Submissions by phenotype
not provided Uncertain:4
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 21, 2022 | 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) - |
Uncertain significance, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Hypertrophic cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 23, 2022 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 30, 2023 | 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 12, 2019 | 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. - |
Prolonged QT interval Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Human Genetics, University of Leuven | Apr 30, 2017 | - - |
Left ventricular noncompaction 10 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | 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. - |
Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 11, 2021 | - - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 16, 2023 | 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. - |
Hypertrophic cardiomyopathy 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | 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. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 18, 2023 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at