The p.V1125M variant (also known as c.3373G>A), located in coding exon 31 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 3373. The valine at codon 1125 is replaced by methionine, an amino acid with highly similar properties. This variant was reported in individual(s) with features consistent with hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) (Gómez J et al. Circ Cardiovasc Genet, 2017 Apr;10; Walsh R et al. Genet. Med., 2017 02;19:192-203; Mahdieh N et al. J. Clin. Lab. Anal., 2018 Mar; Mazzarotto F et al. Genet Med. 2019 Feb;21(2):284-292; Helms AS et al. Circ Genom Precis Med. 2020 Oct;13(5):396-405; Ambry internal data). This variant co-occurred with a second MYBPC3 variant in affected members of a family with HCM, while the p.V1125M variant occurred alone in one individual with borderline hypertrophy (Frank-Hansen R et al. Eur. J. Hum. Genet., 2008 Sep;16:1062-9). This variant was reported in an individual with Fabry disease and HCM who also had a GLA mutation and a second MYBPC3 variant (Favalli V et al. J. Am. Coll. Cardiol., 2016 09;68:1037-50). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.

This missense variant replaces valine with methionine at codon 1125 of the MYBPC3 protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 22267749, 27532257, 28356264, 32841044, 33782553). Some of these individuals also carried a different pathogenic splice variant in the same gene (PMID: 22267749). This variant has also been reported in an individual affected with dilated cardiomyopathy (PMID: 29493010), in an individual affected with suspected drug-induced long QT syndrome (PMID: 31376648), and in an individual affected with sudden unexplained death (PMID: 28807990). This variant has been identified in 7/273636 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 valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1125 of the MYBPC3 protein (p.Val1125Met). This variant is present in population databases (rs121909378, gnomAD 0.01%). This missense change has been observed in individuals with MYBPC3-related conditions (PMID: 28356264, 29493010, 33782553; internal data). ClinVar contains an entry for this variant (Variation ID: 8604). 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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

This variant is classified as VUS-3B. Evidence in support of pathogenic classification: Variant is present in gnomAD <0.01 (v4: 34 heterozygote(s), 0 homozygote(s)). Additional information: Variant is predicted to result in a missense amino acid change from Val to Met; This variant is heterozygous; This gene is associated with both recessive and dominant disease. Dominant inheritance is frequently reported in adult onset conditions and recessive inheritance results in a more severe early onset phenotype (OMIM); Alternative amino acid change(s) at the same position are present in gnomAD (highest allele count: v4: 12 heterozygote(s), 0 homozygote(s)); Previous evidence of pathogenicity for this variant is inconclusive. This variant has been classified as a VUS by multiple clinical laboratories in ClinVar, as well as likely pathogenic. It has been reported in individuals from large cohorts of patients with HCM (PMIDs: 32841044, 29875424, 28356264), and in an individual with HCM who harboured a pathogenic variant in MYPBC3 (PMID: 18337725). This variant has also been reported in individuals with DCM, which has a limited association with MYPBC3 (PMIDs: 29493010, 25163546, PanelApp), as a secondary finding in individuals without MYPBC3-related symptoms (PMIDs: 39486665, 35629155, 32355288, 26633542), in an individual with Fabry disease who had a pathogenic variant in GLA (PMID: 27585509), and in an individual with assumed drug-induced LQTS (PMID: 31376648); No published functional evidence has been identified for this variant; Other missense variant(s) comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. p.(Val1125Leu) and p.(Val1125Ala) have been classified as VUS by clinical laboratories in ClinVar. p.(Val1125Leu) has also been reported in an individual with HCM, where it was classified as a VUS (PMID: 33495596); Variant is located in the annotated fibronectin type III domain (DECIPHER). - Missense variant with inconclusive in silico prediction and/or uninformative conservation; Loss of function is a known mechanism of disease in this gene and is associated with hypertrophic cardiomyopathy 4 (HCM; MIM#115197); Variants in this gene are known to have variable expressivity (PMID: 32841044); Inheritance information for this variant is not currently available in this individual.

Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in one infant who died of SIDS (Dewar 2017). It was also reported in one Iranian individual with DCM where an in silico study showed that it might be pathogenic (Mahdieh 2018). The variant has also been reported in a patient who was compound het for this variant and the c.960-1G>C variant. Her brother also had both variants and was affected but her mother and son who only had the c.906-1G>C variant were unaffected. Her nephew who had just the V1125M variant was mildly affected (Frank-Hansen 2008). Classified as VUS favour pathogenic in Walsh 2017. Clinvar: VUS (GeneDx, Invitae). Gnomad: 0.01% (1 allele).

This missense variant replaces valine with methionine at codon 1125 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 22267749, 27532257, 28356264, 32841044, 33782553). Some of these individuals also carried a different pathogenic variant in the same gene (PMID: 22267749). This variant has also been reported in an individual affected with dilated cardiomyopathy (PMID: 29493010), in an individual affected with suspected drug-induced long QT syndrome (PMID: 31376648), and in an individual affected with sudden unexplained death (PMID: 28807990). This variant has been identified in 7/273636 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.

In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21415409, 27532257, 28807990, 29493010, 22267749, 28356264, 31376648, 34426522, 33782553, 35653365, 27585509, 18337725)

BP4