ClinVar Genomic variation as it relates to human health

Variant classified as Uncertain Significance - Favor Pathogenic. The Ile659Thr v ariant in MYBPC3 has not been reported in the literature nor been detected in la rge and broad populations (European and African American) screened by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS). This low frequency is consistent with a disease causing role but insufficient to establish this wit h confidence. Our laboratory has identified this variant 1 infant with DCM. Comp utational analyses (biochemical amino acid properties, conservation, AlignGVGD, and SIFT) suggest that this variant may impact the protein, though this informat ion is not predictive enough to determine pathogenicity. Additional studies are needed to fully assess its clinical significance.

Variant summary: MYBPC3 c.1976T>C (p.Ile659Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249216 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1976T>C has been reported in the literature as a variant of uncertain clinical significance (VUS) in at-least one individual with a clinical diagnosis of Dilated Cardiomyopathy who underwent a comprehensive genetic assessment on a panel of 19 genes at a reference laboratory (example, Pugh_2014). This individual has been subsequently cited by others (example, Walsh_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 42590; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27532257, 24503780)

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 659 of the MYBPC3 protein (p.Ile659Thr). This variant is present in population databases (rs397515941, gnomAD 0.007%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 24503780, 27532257; Invitae). ClinVar contains an entry for this variant (Variation ID: 42590). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

This missense variant replaces isoleucine with threonine at codon 659 of the MYBPC3 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least 1 individual affected with dilated cardiomyopathy (PMID: 27532257). This variant has been identified in 1/31386 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

The p.I659T variant (also known as c.1976T>C), located in coding exon 21 of the MYBPC3 gene, results from a T to C substitution at nucleotide position 1976. The isoleucine at codon 659 is replaced by threonine, an amino acid with similar properties. This variant has been detected in an infant with dilated cardiomyopathy; however it was also detected in the unaffected mother, and the proband's father was reported to have left ventricular hypertrophy (Pugh TJ et al. Genet. Med., 2014 Aug;16:601-8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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.Ile659Thr This variant is novel. This variant results in isoleucine at codon 659 replaced by threonine, an amino acid with a few similar properties. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. Mutation taster predicts this variant to be disease-causing. The isoleucine at codon 659 is conserved across species, as are neighboring amino acids. No other variants have been reported in association with disease at this codon or at nearby codons. In total the variant has not been seen in ~6,500 individuals from publicly available population datasets. There is no variation at codon 659 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 9/20/13). Note that this dataset does not match the patient's ancestry (Mexico/N. American). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 9/20/13).