ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.646G>A (p.Ala216Thr) (rs201098973)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000035655 SCV000059306 likely benign not specified 2016-08-22 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
CSER _CC_NCGL, University of Washington RCV000148666 SCV000190390 uncertain significance Primary familial hypertrophic cardiomyopathy 2014-06-01 criteria provided, single submitter research Low GERP score may suggest that this variant may belong in a lower pathogenicity class
GeneDx RCV000585965 SCV000208235 likely benign not provided 2021-05-06 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 25637381, 24503780, 18409188, 28807990, 23527136, 24055113, 23233322, 20433692, 25342278, 20738943, 20530761, 26654849, 23299917, 23782526, 24793961, 22765922, 22958901, 27574918, 28416588, 30446606)
Invitae RCV001084987 SCV000284249 likely benign Hypertrophic cardiomyopathy 2019-12-31 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000035655 SCV000696333 likely benign not specified 2021-06-21 criteria provided, single submitter clinical testing Variant summary: MYBPC3 c.646G>A (p.Ala216Thr) results in a non-conservative amino acid change located in the Immunoglobulin subtype domain (IPR003599) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00037 in 240462 control chromosomes, predominantly at a frequency of 0.0027 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYBPC3 causing Cardiomyopathy phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.646G>A has been reported in the literature in individuals affected with Cardiomyopathy however, without strong evidence for pathogenicity (example: Bick_2012, Pugh_2014). Co-occurrence with another pathogenic variant has been reported (MYBPC3 c.772G>A , p.E258K), providing supporting evidence for a benign role (Nunez_2013). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven other ClinVar submitters (evaluation after 2014) cite the variant as likely benign (n=6) or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics RCV000621185 SCV000736916 likely benign Cardiovascular phenotype 2018-08-27 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000148666 SCV000747990 uncertain significance Primary familial hypertrophic cardiomyopathy 2016-12-20 criteria provided, single submitter clinical testing
Color Health, Inc RCV000771261 SCV000903376 benign Cardiomyopathy 2018-04-07 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001106360 SCV001263419 likely benign Familial hypertrophic cardiomyopathy 4 2019-08-14 criteria provided, single submitter clinical testing 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Clinical Services Laboratory,Illumina RCV001106361 SCV001263420 likely benign Left ventricular noncompaction 10 2019-08-14 criteria provided, single submitter clinical testing 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000585965 SCV001744658 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics,Academic Medical Center RCV000585965 SCV001918759 likely benign not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000585965 SCV001927286 likely benign not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000585965 SCV001955946 likely benign not provided no assertion criteria provided clinical testing

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