Submissions for variant NM_000256.3(MYBPC3):c.624G>C (p.Gln208His)

gnomAD frequency: 0.00020  dbSNP: rs202139499

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172014	SCV000054775	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035651	SCV000059302	uncertain significance	not specified	2016-04-25	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Gln208His variant in MYBPC3 has been previously identified by our laboratory in 3 individ uals with HCM. One of these individuals carried an additional disease-causing va riant, and had an earlier age of onset than an affected parent, suggesting that the p.Gln208His variant may modify severity or independently cause disease. It has also been identified in 17/62206 European chromosomes by the Exome Aggregati on Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs202139499). This va riant was predicted to be benign using a computational tool clinically validated by our laboratory. This tool's benign prediction is estimated to be correct 89% of the time (Jordan 2011). In summary, while there is some suspicion for a path ogenic role, the clinical significance of the p.Gln208His variant is uncertain.
GeneDx	RCV000172014	SCV000208233	likely benign	not provided	2020-09-11	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24033266, 21415409, 23299917, 23861362, 27153395, 27884173, 25637381, 22958901, 25558701, 28518168, 31513939)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000234354	SCV000284248	likely benign	Hypertrophic cardiomyopathy	2025-01-27	criteria provided, single submitter	clinical testing
Center for Human Genetics, University of Leuven	RCV000234354	SCV000886814	uncertain significance	Hypertrophic cardiomyopathy	2018-10-31	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769356	SCV000900744	uncertain significance	Cardiomyopathy	2023-01-03	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000769356	SCV000904590	likely benign	Cardiomyopathy	2018-07-02	criteria provided, single submitter	clinical testing
Mendelics	RCV000988554	SCV001138318	uncertain significance	Hypertrophic cardiomyopathy 4	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001106362	SCV001263421	likely benign	Left ventricular noncompaction 10	2017-04-27	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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000988554	SCV001263422	uncertain significance	Hypertrophic cardiomyopathy 4	2017-04-27	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV000172014	SCV002541141	uncertain significance	not provided	2023-01-13	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002362619	SCV002658686	likely benign	Cardiovascular phenotype	2018-04-19	criteria provided, single submitter	clinical testing	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000035651	SCV003934388	likely benign	not specified	2025-02-10	criteria provided, single submitter	clinical testing	Variant summary: MYBPC3 c.624G>C (p.Gln208His) results in a non-conservative amino acid change located in the Immunoglobulin-like domain (IPR003599) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00022 in 275114 control chromosomes, predominantly at a frequency of 0.0046 within the Ashkenazi Jewish subpopulation in the gnomAD database. The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 4.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYBPC3 causing Cardiomyopathy phenotype (0.001). In addition, the variant has been reported in a Saudi Arabian cohort of individuals who lacked the reported phenotype with an allele frequency of ~0.03, including 1 homozygote (Abouelhoda_2016). The following publication have been ascertained in the context of this evaluation (PMID: 27884173). ClinVar contains an entry for this variant (Variation ID: 42775). Based on the evidence outlined above, the variant was classified as likely benign.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV005394217	SCV006054946	uncertain significance	Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10	2020-08-25	criteria provided, single submitter	research
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000035651	SCV006066620	likely benign	not specified	2025-04-09	criteria provided, single submitter	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148684	SCV000190410	uncertain significance	Primary familial hypertrophic cardiomyopathy	2014-06-01	no assertion criteria provided	research
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000035651	SCV000280275	uncertain significance	not specified	2012-03-05	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. MYBPC3 p.Gln208His Given the weak case data and the presence in the general population (both reviewed below), we also consider it a variant of unknown significance. I found two unpublished online reports (and no published reports) of the variant in patients with HCM. The variant is listed in the Seidman's online database (http://genepath.med.harvard.edu/~seidman/outdated-mutdb/muts/MYBPC3_Gln208His.html). It appears that they observed this in their cohort, though that is not completely clear and no details are provided. I also found a presentation online by Arad et al that suggests they observed the variant in their Jewish cohort (http://www.his-files.com/pdf/annual2013/presentations/1720_Michael_Arad_schwartz.pdf). The patient also had a TNNI3 variant. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging (with a score of 1.0); the Grantham score is 24. The glutamine at codon 624 is conserved across species. In total the variant has been reported in 6 of 7243 individuals from publicly available population datasets with ~0.1% of Caucasians carrying the variant. The variant was reported online in 5 of 4219 Caucasian individuals and 0 of 2112 African-American individuals in the NHLBI Exome Sequencing Project dataset (as of January 3rd, 2014). The phenotype of those individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in this dataset so this does not necessarily rule out pathogenicity (Pan et al 2012). The variant was observed in 1 in 912 individuals in the NIH ClinSeq cohort (Ng et al 2013). The variant is listed in dbSNP (rs202139499) with entries for the ESP and ClinSeq data as well as a submission from LMM.
Cohesion Phenomics	RCV000234354	SCV003803626	likely benign	Hypertrophic cardiomyopathy	2022-09-27	no assertion criteria provided	clinical testing