rs727503208
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PP3_Moderate
The NM_000256.3(MYBPC3):c.1123G>A(p.Val375Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000242 in 1,612,772 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. V375E) 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 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYBPC3 | NM_000256.3 | c.1123G>A | p.Val375Met | missense_variant | 13/35 | ENST00000545968.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.1123G>A | p.Val375Met | missense_variant | 13/35 | 5 | NM_000256.3 | P4 | |
MYBPC3 | ENST00000399249.6 | c.1123G>A | p.Val375Met | missense_variant | 12/34 | 5 | A2 | ||
MYBPC3 | ENST00000544791.1 | c.1123G>A | p.Val375Met | missense_variant, NMD_transcript_variant | 13/27 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152096Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000162 AC: 4AN: 246640Hom.: 0 AF XY: 0.0000224 AC XY: 3AN XY: 134108
GnomAD4 exome AF: 0.0000246 AC: 36AN: 1460676Hom.: 0 Cov.: 45 AF XY: 0.0000179 AC XY: 13AN XY: 726534
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152096Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74310
ClinVar
Submissions by phenotype
Cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 07, 2023 | This missense variant replaces valine with methionine at codon 375 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 at least 3 individuals affected with hypertrophic cardiomyopathy (PMID: 25351510, 27532257) and in an individual affected with dilated cardiomyopathy (PMID: 27532257, 31983221). This variant has been identified in 5/278004 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Oct 17, 2022 | - - |
Hypertrophic cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Oct 30, 2023 | This missense variant replaces valine with methionine at codon 375 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 at least 3 individuals affected with hypertrophic cardiomyopathy (PMID: 25351510, 27532257) and in an individual affected with dilated cardiomyopathy (PMID: 27532257, 31983221). This variant has been identified in 5/278004 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2024 | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 375 of the MYBPC3 protein (p.Val375Met). This variant is present in population databases (rs727503208, gnomAD 0.004%). This missense change has been observed in individual(s) with dilated cardiomyopathy and/or hypertrophic cardiomyopathy (PMID: 25351510, 27532257, 31983221). ClinVar contains an entry for this variant (Variation ID: 164128). 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 18, 2014 | The Val375Met variant in MYBPC3 has not been previously reported in individuals with cardiomyopathy or in large population studies. Computational prediction too ls and conservation analysis suggest that this variant may impact the protein, t hough this information is not predictive enough to determine pathogenicity. In s ummary, the clinical significance of the Val375Met variant is uncertain. - |
Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 13, 2021 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 01, 2022 | Identified among cohorts of patients with HCM and DCM (Lopes et al., 2015; Walsh et al., 2017; Mazzarotto et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); 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: 25351510, 27532257, 28679633, 31983221) - |
Hypertrophic cardiomyopathy 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Clinical Genomics Laboratory, Washington University in St. Louis | Jan 27, 2024 | The MYBPC3 c.1123G>A (p.Val375Met) variant has been reported in several individuals with cardiomyopathy (Lopes LR et al., PMID: 25351510; Walsh R et al., PMID: 27532257; Mazzarotto F et al., PMID: 31983221). This variant has been reported in the ClinVar database as a variant of uncertain significance by multiple submitters (ClinVar Variation ID: 164128). This variant is observed on 39/1,612,772 alleles in the general population (gnomAD v4.0.0). Computational predictors are uncertain as to the impact of this variant on MYBPC3 function. Due to limited information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of the MYBPC3 c.1123G>A (p.Val375Met) variant is uncertain at this time. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 04, 2022 | The p.V375M variant (also known as c.1123G>A), located in coding exon 13 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 1123. The valine at codon 375 is replaced by methionine, an amino acid with highly similar properties. This alteration has been reported in hypertrophic cardiomyopathy (HCM) and dilated cardiomyopahty (DCM) cohorts; however, clinical details were limited (Lopes LR et al. Heart, 2015 Feb;101:294-301; Walsh R et al. Genet. Med., 2017 02;19:192-203). 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