The c.2938C>T (p.R980C) alteration is located in exon 28 (coding exon 28) of the MYBPC3 gene. This alteration results from a C to T substitution at nucleotide position 2938, causing the arginine (R) at amino acid position 980 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

This missense variant replaces arginine with cysteine at codon 980 of the MYBPC3 protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with hypertrophic cardiomyopathy (PMID: 27532257, 33782553), in one individual affected with dilated cardiomyopathy (PMID: 32880476), in one individual affected with isolated left ventricular dysfunction (PMID: 22958901), and in one individual affected with unspecified heart disease (PMID: 29540472). This variant has been identified in 6/233074 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.

Variant summary: MYBPC3 c.2938C>T (p.Arg980Cys) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 2.2e-05 in 1585082 control chromosomes. This frequency is not significantly higher than estimated for disease-causing variants in MYBPC3, allowing no conclusion about variant significance. c.2938C>T has been observed in individuals affected with Hypertrophic Cardiomyopathy (Walsh_2017), Dilated Cardiomyopathy (Verdonschot_2018), or Left Ventricular Dysfunction (Bick_2012). These reports 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. The following publications have been ascertained in the context of this evaluation (PMID: 22958901, 37652022, 32880476, 30571196, 27532257). ClinVar contains an entry for this variant (Variation ID: 42671). Based on the evidence outlined above, the variant was classified as uncertain significance.

The Arg980Cys variant in MYBPC3 has not been previously reported in the literatu re nor previously been identified in >3600 individuals (>2200 Caucasian, >300 Bl ack) tested by our laboratory. Computational analyses (biochemical amino acid pr operties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that this varian t may impact the protein, though this information is not predictive enough to de termine pathogenicity conclusively. Additional information is needed to fully as sess the clinical significance of the Arg980Cys variant.

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Reported in association with left ventricular dysfunction (Bick et al., 2012; Hazbroek et al., 2018), HCM (Walsh et al., 2017), and DCM (Verdonschot et al., 2020) in published literature; 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, 29540472, 22958901, 32880476)

This missense variant replaces arginine with cysteine at codon 980 of the MYBPC3 protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with hypertrophic cardiomyopathy (PMID: 27532257, 33782553), in one individual affected with dilated cardiomyopathy (PMID: 32880476), in one individual affected with isolated left ventricular dysfunction (PMID: 22958901), and in one individual affected with unspecified heart disease (PMID: 29540472). This variant has been identified in 6/233074 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.

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 980 of the MYBPC3 protein (p.Arg980Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with abnormal left ventricular wall thickness, diameter, and/or function (PMID: 22958901, 27532257, 29540472, 32880476, 37652022). ClinVar contains an entry for this variant (Variation ID: 42671). 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.