rs374946555
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3
The NM_000256.3(MYBPC3):c.2807C>T(p.Thr936Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000254 in 1,612,640 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T936K) has been classified as Uncertain significance.
Frequency
Consequence
NM_000256.3 missense
Scores
Clinical Significance
Conservation
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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.2807C>T | p.Thr936Met | missense_variant | 27/35 | ENST00000545968.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.2807C>T | p.Thr936Met | missense_variant | 27/35 | 5 | NM_000256.3 | P4 | |
MYBPC3 | ENST00000399249.6 | c.2807C>T | p.Thr936Met | missense_variant | 26/34 | 5 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000854 AC: 13AN: 152154Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000404 AC: 10AN: 247610Hom.: 0 AF XY: 0.0000595 AC XY: 8AN XY: 134470
GnomAD4 exome AF: 0.0000192 AC: 28AN: 1460486Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15AN XY: 726522
GnomAD4 genome ? AF: 0.0000854 AC: 13AN: 152154Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6AN XY: 74330
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 16, 2023 | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 936 of the MYBPC3 protein (p.Thr936Met). This variant is present in population databases (rs374946555, gnomAD 0.02%). This missense change has been observed in individual(s) with sudden unexplained death, left ventricular hypertrabeculation and dilated cardiomyopathy (PMID: 25163546, 28798025, 35934244). ClinVar contains an entry for this variant (Variation ID: 181130). 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 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 | Dec 13, 2023 | This missense variant replaces threonine with methionine at codon 936 of the MYBPC3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 30847666), in an individual affected with left ventricular hypertrabeculation (PMID: 28798025), in an individual affected with sudden unexplained death (PMID: 35934244), an in an individual affected with heart disease (PMID: 22958901). This variant has been identified in 11/278986 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. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 07, 2023 | This missense variant replaces threonine with methionine at codon 936 of the MYBPC3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 30847666), in an individual affected with left ventricular hypertrabeculation (PMID: 28798025), in an individual affected with sudden unexplained death (PMID: 35934244), an in an individual affected with heart disease (PMID: 22958901). This variant has been identified in 11/278986 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;C3715165:Left ventricular noncompaction 10 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 14, 2021 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 23, 2015 | This mutation is denoted p.Thr936Met (ACG>ATG): c.2807 C>T in exon 27 of the MYBPC3 gene (NM_000256.3). The T936M variant has not been published as a mutation or been reported as a benign polymorphism to our knowledge. The T936M variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The T936M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other 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. Mutations in nearby residues (R943Q, R939W) have been reported in association with HCM, further supporting the functional importance of this region of the protein. Nevertheless, the T936M variant has been reported as a variant of unknown significance in a 71 year old without clincal features of HCM (Bick A et al. 2012). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant.The variant is found in CARDIOMYOPATHY panel(s). - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 11, 2021 | The p.T936M variant (also known as c.2807C>T), located in coding exon 27 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 2807. The threonine at codon 936 is replaced by methionine, an amino acid with similar properties. This variant has been reported in a variety of cardiac disease and genetic testing cohorts, including individuals with dilated cardiomyopathy, hypertrophic cardiomyopathy, and left ventricular non-compaction /hypertrabeculation; however, clinical details were limited and additional cardiac variants were detected in some cases (Haas J et al. Eur Heart J, 2015 May;36:1123-35a; Miszalski-Jamka K et al. Circ Cardiovasc Genet, 2017 Aug;10:[Epub ahead of print]; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309).This alteration has also been reported in an individual without evidence of hypertrophic cardiomyopathy from a large prospective cardiovascular disease cohort (Bick AG et al. Am. J. Hum. Genet., 2012 Sep;91:513-9). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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