ClinVar Genomic variation as it relates to human health

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.

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.

MYBPC3: BP4, BS2

Low GERP score may suggest that this variant may belong in a lower pathogenicity class

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 20433692, 21511876, 20474083, 29710196, 22958901, 24119082, 23861362, 24055113, 23299917, 25637381, 25569433, 27194543, 29121657, 24503780, 28679633, 18957093, 22267749, 21835320, 33232181)

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 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 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, Khan_2022). The variant did not segregate with disease in two cardiomyopathy families (internal testing). At least one co-occurrence with a pathogenic variant has been reported in the literature (TTN [NM_001256850.1] c.102712C>T, p.Gln34238X; Khan_2022), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign and five ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.

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.

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.

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.