rs730880623
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate
The NM_000256.3(MYBPC3):c.604A>C(p.Lys202Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000515 in 1,611,404 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. K202R) 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 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYBPC3 | NM_000256.3 | c.604A>C | p.Lys202Gln | missense_variant | 5/35 | ENST00000545968.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.604A>C | p.Lys202Gln | missense_variant | 5/35 | 5 | NM_000256.3 | P4 | |
MYBPC3 | ENST00000399249.6 | c.604A>C | p.Lys202Gln | missense_variant | 5/34 | 5 | A2 | ||
MYBPC3 | ENST00000544791.1 | c.604A>C | p.Lys202Gln | missense_variant, NMD_transcript_variant | 5/27 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000591 AC: 9AN: 152268Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000367 AC: 9AN: 245380Hom.: 0 AF XY: 0.0000449 AC XY: 6AN XY: 133700
GnomAD4 exome AF: 0.0000507 AC: 74AN: 1459136Hom.: 0 Cov.: 31 AF XY: 0.0000482 AC XY: 35AN XY: 725960
GnomAD4 genome ? AF: 0.0000591 AC: 9AN: 152268Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74394
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 05, 2019 | The p.Lys202Gln variant in MYBPC3 has been reported in 1 individual with DCM. This variant has also been identified in 5/62340 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs730880623). Computational prediction tools and conservation analysis suggest that the variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Lys202Gln variant is uncertain. - |
Uncertain significance, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Apr 24, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 13, 2021 | Reported in association with DCM in the published literature (Hershberger et al., 2010; Ito et al., 2017; Ramchand et al., 2020; Mazzaroatto et al., 2020) and in a participant in the Framington Heart Study (Bick et al., 2012); Reported in ClinVar (ClinVar Variant ID# 181046; ClinVar); 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: 22958901, 20215591, 31931689, 28679633, 31983221) - |
Hypertrophic cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 11, 2024 | This missense variant replaces lysine with glutamine at codon 202 of the MYBPC3 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in two individuals affected with dilated cardiomyopathy (PMID: 20215591, 31983221). This variant has also been identified in 10/276772 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 | Oct 22, 2023 | This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 202 of the MYBPC3 protein (p.Lys202Gln). This variant is present in population databases (rs730880623, gnomAD 0.008%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 20215591, 31931689, 31983221). ClinVar contains an entry for this variant (Variation ID: 181046). 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. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 12, 2023 | This missense variant replaces lysine with glutamine at codon 202 of the MYBPC3 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with dilated cardiomyopathy (PMID: 20215591, 31983221). This variant has been identified in 10/276772 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. - |
Dilated cardiomyopathy 1A Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | May 11, 2015 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 14, 2022 | The p.K202Q variant (also known as c.604A>C), located in coding exon 5 of the MYBPC3 gene, results from an A to C substitution at nucleotide position 604. The lysine at codon 202 is replaced by glutamine, an amino acid with similar properties. This alteration has been detected in dilated cardiomyopathy (DCM) cohorts; however, clinical details were limited (Hershberger RE et al. Circ Cardiovasc Genet. 2010;3:155-61; Mazzarotto F et al. Circulation, 2020 02;141:387-398; Ramchand J et al. J Am Heart Assoc, 2020 01;9:e013346). This variant has also been identified in individuals without overt clinical features of DCM (Bick AG et al. Am. J. Hum. Genet. 2012;91:513-9). This amino acid position is highly 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. - |
MYBPC3-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 28, 2022 | The MYBPC3 c.604A>C variant is predicted to result in the amino acid substitution p.Lys202Gln. This variant has been reported in individuals with dilated cardiomyopathy (Hershberger et al. 2010. PubMed ID: 20215591; Dataset S6, Ito et al. 2017. PubMed ID: 28679633; Table S3, Mazzarotto et al. 2020. PubMed ID: 31983221; Table S2, Bick et al. 2012. PubMed ID: 22958901; Table S4, Ramchand et al. 2020. PubMed ID: 31931689). This variant is reported in 0.0079% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-47371375-T-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at