rs199865688
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 4P and 6B. PM1PM5BP4_ModerateBS2
The NM_000256.3(MYBPC3):c.2497G>A(p.Ala833Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00178 in 1,614,052 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A833V) has been classified as Likely benign.
Frequency
Consequence
NM_000256.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYBPC3 | NM_000256.3 | c.2497G>A | p.Ala833Thr | missense_variant | 25/35 | ENST00000545968.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.2497G>A | p.Ala833Thr | missense_variant | 25/35 | 5 | NM_000256.3 | P4 | |
MYBPC3 | ENST00000399249.6 | c.2497G>A | p.Ala833Thr | missense_variant | 24/34 | 5 | A2 | ||
MYBPC3 | ENST00000544791.1 | c.*2G>A | 3_prime_UTR_variant, NMD_transcript_variant | 25/27 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00117 AC: 178AN: 152250Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.00150 AC: 373AN: 249150Hom.: 0 AF XY: 0.00138 AC XY: 187AN XY: 135146
GnomAD4 exome AF: 0.00185 AC: 2703AN: 1461684Hom.: 6 Cov.: 33 AF XY: 0.00185 AC XY: 1344AN XY: 727132
GnomAD4 genome ? AF: 0.00117 AC: 178AN: 152368Hom.: 0 Cov.: 31 AF XY: 0.00115 AC XY: 86AN XY: 74514
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:7
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | May 10, 2022 | See Variant Classification Assertion Criteria. - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jun 11, 2021 | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2021 | - - |
Hypertrophic cardiomyopathy 4 Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Mar 22, 2018 | 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. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2010 | - - |
Cardiomyopathy Benign:2
Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Mar 06, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 23, 2018 | - - |
Primary familial hypertrophic cardiomyopathy Benign:2
Likely benign, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
Likely benign, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jun 24, 2013 | - - |
Cardiomyopathy, dilated, 1MM Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2010 | - - |
Left ventricular noncompaction 10 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Nov 21, 2018 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 27, 2015 | p.Ala833Thr in exon 25 of MYBPC3: The significance of this variant was initially debated, as it was reported in 4 individuals with HCM, 3 of whom carried a seco nd variant (Morner 2003, Alders 2003, Andersen 2004, Van Driest 2004). Our labor atory has identified this variant in multiple individuals with various types of cardiomyopathies (HCM, DCM, and LVNC), some of whom also carried a second varian t. The frequent occurrence of a variant in conjunction with additional disease-c ausing variants argues against a pathogenic role when present in isolation as do es its identification in individuals with HCM, LVNC and DCM as these cardiomyopa thies are caused by different defects at the cellular level. Finally, this varia nt has been identified in 0.2% (182/66666) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs199865688) . In summary, the overall evidence suggests that the p.Ala833Thr variant is like ly benign, though we cannot rule out that it may modify disease severity when pr esent with other cardiomyopathy variants. - |
Primary dilated cardiomyopathy Benign:1
Likely benign, no assertion criteria provided | clinical testing | Blueprint Genetics | Sep 04, 2014 | - - |
Hypertrophic cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 26, 2019 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Paroxysmal atrial fibrillation Benign:1
Likely benign, no assertion criteria provided | clinical testing | Blueprint Genetics | Sep 04, 2014 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at