ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.2870C>G (p.Thr957Ser) (rs193922380)

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000030285 SCV000050986 likely benign Primary familial hypertrophic cardiomyopathy 2013-06-24 criteria provided, single submitter research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000035534 SCV000052952 likely benign not specified 2021-01-28 criteria provided, single submitter clinical testing Variant summary: MYBPC3 c.2870C>G (p.Thr957Ser) results in a conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.001 in 235526 control chromosomes, predominantly at a frequency of 0.0017 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2-fold 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 Non-Finnish European origin. c.2870C>G has been reported in the literature in individuals affected with Cardiomyopathy without strong evidence for causality (e.g. Ehlermann_2008, Rodriguez-Garcia_2010, Gruner_2011, Olivotto_2011, Merlo_2013, Pugh_2014, Earle_2015, Haas_2015, Medeiros-Domingo_2017, Mazzarotto_2019). The variant did not segregate with disease in two cardiomyopathy families (internal testing). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 14 other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. These laboratories cited the variant as benign/likely benign (n=8) and uncertain significance (n=6). Based on the evidence outlined above, the variant was classified as likely benign.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035534 SCV000059184 likely benign not specified 2017-08-06 criteria provided, single submitter clinical testing The p.Thr957Ser variant in MYBPC3 has been reported in individuals with HCM (Ehl ermann 2008, Rodriguez-Garcia 2010, Olivotto 2011, Gruner 2011) and DCM (Merlo 2 013) but has also identified in 0.2% (187/120848) of European chromosomes by the gnomAD (gnomad.broadinstitute.org; dbSNP rs193922380). Threonine (Thr) at posit ion 957 is not conserved in evolution and 2 species (Chinese tree shrew and Mexi can tetra) carry a serine (Ser) at this position, supporting that a change at th is position may be tolerated. In summary, while the clinical significance of the p.Thr957Ser variant is not conclusive, these data suggest that it is likely ben ign.
CSER _CC_NCGL, University of Washington RCV000030285 SCV000190382 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 RCV000035534 SCV000208126 likely benign not specified 2018-02-22 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV001086258 SCV000284235 likely benign Hypertrophic cardiomyopathy 2020-12-03 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000487942 SCV000332272 uncertain significance not provided 2015-06-15 criteria provided, single submitter clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000415634 SCV000493760 uncertain significance Left ventricular noncompaction 10 2015-08-13 criteria provided, single submitter clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000415668 SCV000493761 uncertain significance Familial hypertrophic cardiomyopathy 4 2015-08-13 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000487942 SCV000574880 uncertain significance not provided 2020-10-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000622091 SCV000737108 likely benign Cardiovascular phenotype 2018-04-16 criteria provided, single submitter clinical testing Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;In silico models in agreement (benign)
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000035534 SCV000747989 likely benign not specified 2017-06-12 criteria provided, single submitter clinical testing
Color Health, Inc RCV000776144 SCV000911138 likely benign Cardiomyopathy 2018-05-30 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282756 SCV001159842 likely benign none provided 2020-07-10 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000415668 SCV001259730 uncertain significance Familial hypertrophic cardiomyopathy 4 2018-12-06 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. 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.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000776144 SCV001332747 benign Cardiomyopathy 2017-11-02 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000035534 SCV000280247 uncertain significance not specified 2015-06-19 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. p.Thr957Ser (T957S; c.2870C>G) in exon 27 of the gene MYBPC3 (NM_000256.3) We re-reviewed the variant on 8/17/2015 and conclude it is variant of uncertain significance, but probably benign. In summary, the reasons for this are: Disease-causing variants in MYBPC3 are more likely to be truncating than missense; this missense variant is at a non-conserved residue and Serine is the standard amino acid in at least two species; the variant is more common in the Caucasian population than HCM. Thr957Ser in the MYBPC3 gene has been reported previously in at least 4 unrelated individuals with HCM, including as a VUS (Ehlermann et al. 2008, Rodriguez-Garcia et al. 2010, Olivotto et al. 2011, Gruner et al. 2011). There is no segregation data available in these papers. Ehlermann et al. reported it in one patient with HCM and did not observe it in 430 control individuals. Rodriguez-Garcia found it in one individual with HCM but reported it to have an uncertain pathogenic effect. Olivotto et al. reported it in one patient with HCM. Gruner et al. identified it in an individual with apical HCM and classified it as a VUS. In ClinVar, the Laboratory for Molecular Medicine (LMM) reports that it has identified this variant in 14 adults with HCM or DCM. However, they add, 5 of these individuals carried another variant sufficient to explain their disease. Thr957Ser results in a conservative amino acid change of a neutral, polar Threonine with a neutral, polar Serine at a position that is not conserved across species. In fact, the default amino acid is Serine in two species, according to LMM, supporting the idea that a Serine at this position may be tolerated. A variant at a neighboring residue (Thr958Ile) has been reported in association with HCM as have the variants Asn948Thr and Pro961Leu (Stenson et al. 2003), supporting the potential functional importance of this region of the protein. However, the NHLBI ESP Variant Server reports Thr957Ser in 11 out of 8,273 alleles from individuals of European background, indicating that it may be a benign variant. The ESP dataset currently includes variant calls on ~4200 Caucasian and ~2000 African American individuals. The phenotype of the ESP 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. Variation at this codon has also been seen frequently in the ExAC dataset, which currently includes variant calls on ~60,000 individuals of multiple ethnic backgrounds (Latino, European (non-Finnish), Finnish, South Asian, African & East Asian) and includes ESP data. These individuals took part in a range of disease-specific and population genetic studies, and the curators made an effort to exclude individuals with severe pediatric diseases. It is present in 118/54,031 individuals overall, and 98/33,813 Caucasian individuals (our patient is Caucasian); this variant’s allele frequency is therefore over 0.1% among Caucasians, which means it would be present in 0.29% of the population=1/345 individuals. This is greater than the overall prevalence of HCM itself, which is why we suspect the variant is probably benign. In summary, with the clinical and molecular information available at this time we cannot determine whether this variant is a disease-causing mutation or a benign variant—but it seems more likely to be benign. The variant is not appropriate for predictive testing in family members, and no conclusions can be drawn about a patient’s risk for HCM based on this variant.
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV001254752 SCV001430841 benign Primary dilated cardiomyopathy 2019-12-05 no assertion criteria provided research MYBPC3 Thr957Ser is present in the Genome Aggregation Database (http://gnomad.broadinstitute.org/) at an allele frequency of 0.0009. In silico tools SIFT, PolyPhen-HCM and MutationTaster predict this variant to be benign. We have identified MYBPC3 Thr957Ser in a proband who was diagnosed at with DCM and LVNC at birth. Familial segregation within this family revealed 2 affected family members who do have MYBPC3 Thr957Ser, but harbour a pathogenic TNNT2 variant. In summary, we have classified the MYBPC3 Thr957Ser variant as "Benign" based on its frequency in the general population, prediction of in silico tool, and the lack of segregation in our family.

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