chr11-47342683-C-T
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM1PP3BP4_StrongBP6
The NM_000256.3(MYBPC3):c.1519G>A(p.Gly507Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000583 in 1,614,008 control chromosomes in the GnomAD database, including 1 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 nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G507V) has been classified as Uncertain significance.
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.1519G>A | p.Gly507Arg | missense_variant | 17/35 | ENST00000545968.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.1519G>A | p.Gly507Arg | missense_variant | 17/35 | 5 | NM_000256.3 | P4 | |
MYBPC3 | ENST00000399249.6 | c.1519G>A | p.Gly507Arg | missense_variant | 16/34 | 5 | A2 | ||
MYBPC3 | ENST00000544791.1 | c.1519G>A | p.Gly507Arg | missense_variant, NMD_transcript_variant | 17/27 | 5 |
Frequencies
GnomAD3 genomes AF: 0.00168 AC: 255AN: 152192Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000598 AC: 149AN: 249266Hom.: 0 AF XY: 0.000481 AC XY: 65AN XY: 135218
GnomAD4 exome AF: 0.000470 AC: 687AN: 1461698Hom.: 1 Cov.: 31 AF XY: 0.000441 AC XY: 321AN XY: 727134
GnomAD4 genome AF: 0.00167 AC: 254AN: 152310Hom.: 0 Cov.: 33 AF XY: 0.00157 AC XY: 117AN XY: 74478
ClinVar
Submissions by phenotype
not specified Benign:5
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 07, 2014 | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 11, 2024 | Variant summary: MYBPC3 c.1519G>A (p.Gly507Arg) results in a non-conservative amino acid change located in the third immunoglobulin subtype 2 domain (IPR003598) of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00058 in 1607036 control chromosomes, predominantly at a frequency of 0.0054 within the African or African-American subpopulation in the gnomAD database (v4.0 dataset), including 1 homozygote. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 5.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYBPC3 causing Hypertrophic Cardiomyopathy phenotype (0.001), strongly suggesting that the variant is a benign polymorphism. c.1519G>A has been reported in the literature in sequencing studies of individuals affected with and/or undergoing multigene panel testing for Hypertrophic Cardiomyopathy (e.g. Erdmann_2003, Kassem_2013, Lakdawala_2012, Liu_2015). These reports do not provide unequivocal conclusions about association of the variant with Hypertrophic Cardiomyopathy. At-least two co-occurrences with other pathogenic variants have been observed at our laboratory (HCM-MYBPC3 c.2308G>A, p.Asp770Asn; Transthyretin Amylidosis-TTR c.424G>A, p.Val142Ile), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function and demonstrated that the variant didn't destabilize protein structure in an in vitro assay (Suay-Corredera_2021). The following publications have been ascertained in the context of this evaluation (PMID: 23217326, 26332594, 23820649, 22995991, 22763267, 24055113, 12974739, 23233322, 22464770, 26090888, 34097875). ClinVar contains an entry for this variant (Variation ID: 42543). Based on the evidence outlined above, the variant was classified as benign. - |
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 12, 2015 | p.Gly507Arg in exon 17 of MYBPC3: This variant is not expected to have clinical significance because it has been identified in 0.6% (54/9808) of African chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs35736435). - |
Likely benign, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Jul 12, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Hypertrophic cardiomyopathy 4 Uncertain:1Benign:1
Benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Uncertain significance, criteria provided, single submitter | reference population | Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center | Mar 18, 2016 | - - |
Cardiomyopathy Benign:2
Benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Dec 14, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 13, 2018 | - - |
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 15, 2021 | This variant is associated with the following publications: (PMID: 23299917, 12974739, 21310275, 15519027, 17560888, 23217326, 22763267, 23233322, 25637381, 22995991, 24055113, 23820649, 26332594, 30188508) - |
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Mar 28, 2023 | - - |
Hypertrophic cardiomyopathy Benign:2
Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Primary familial hypertrophic cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 01, 2018 | 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. - |
Familial amyloid neuropathy Benign:1
Benign, criteria provided, single submitter | clinical testing | Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego | May 20, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at