Variant classified as Uncertain Significance - Favor Benign. The Arg177Cys varia nt in MYBPC3 has been reported in 1 adult with HCM who carried another pathogeni c variant in the MYBPC3 gene(Cardiogenomics) and was identified by our laborator y in 2 individuals with DCM (Wells 2011, LMM unpublished data), one of whom carr ied a second variant of unknown significance in VCL. In 1 family with DCM this v ariant was found to segregate with disease in 2/3 affected family members. The A rg177Cys variant has been identified in 1/8398 European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs19 3922385). Arginine (Arg) at position 177 not well conserved in mammals or evolut ionarily distant species and the change to cysteine (Cys) was predicted to be be nign using a computational tool clinically validated by our laboratory. This too l's benign prediction is estimated to be correct 89% of the time (Jordan 2011). In addition, another change at the same position (Arg177His) is present in 1% of the general population (42/4088 African American chromosomes, NHLBI Exome Seque ncing Project), suggesting that changes at this position may not affect the prot ein. In summary, while these data argue against a disease-causing role when pres ent in isolation, a modifying effect cannot be ruled out and additional studies are needed to fully establish the clinical significance of this variant.

The c.529C>T (p.R177C) alteration is located in exon 5 (coding exon 5) of the MYBPC3 gene. This alteration results from a C to T substitution at nucleotide position 529, causing the arginine (R) at amino acid position 177 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

PM2

BS1

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 177 of the MYBPC3 protein (p.Arg177Cys). This variant is present in population databases (rs193922385, gnomAD 0.02%). This missense change has been observed in individual(s) with dilated or hypertrophic cardiomyopathy (PMID: 22555271, 24062880, 27532257, 30762279, 32746448, 32880476, 33782553, 36178741). ClinVar contains an entry for this variant (Variation ID: 36613). 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.

Variant summary: MYBPC3 c.529C>T (p.Arg177Cys) results in a non-conservative amino acid change located in the Immunoglobulin subtype domain (IPR003599) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 233730 control chromosomes in gnomAD. This frequency is not significantly higher than estimated for a pathogenic variant in MYBPC3 causing Hypertrophic Cardiomyopathy (6.8e-05 vs 0.001), allowing no conclusion about variant significance. However, another variant at the same residue (p.Arg177His) is present at allele frequency of 1.3% in African subpopulation in gnomAD, strongly suggesting it to be a likely benign polymorphism, thus the residue p.Arg177 may not be critical for protein function. c.529C>T has been reported in the literature in individuals affected with Hypertrophic Cardiomyopathy or Dilated Cardiomyopathy (example: Kindel_2012, Wells_2011, Waning_2018, Alijeaid_2019, Verdonschot_2020, Bursetein_2021, Suay-Corredara_2021). These data do not allow any conclusion about variant significance. Co-occurrences with other pathogenic variants have been reported in our internal data or publications (MYPBC3 c.3811C>T, p.R1271*; MYPBC3 c.1235_1236delTT, p.Ile411_Phe412insTer; RAF1 c.769T>C, p.Ser257Pro) (Kindel_2012, Alijeaid_2019), providing supporting evidence for a benign role. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.

This missense variant replaces arginine with cysteine at codon 177 of the MYBPC3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with hypertrophic cardiomyopathy (PMID: 22555271, 30762279). One of these individuals carried a pathogenic truncating variant in the same gene (PMID: 22555271). This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 24503780, 24062880, 24503780, 27532257, 32746448, 32880476, 36178741). One of these individuals also carried a pathogenic variant in the MYH7 gene (PMID: 36178741). This variant has also been reported in an individual affected with non-compaction cardiomyopathy (PMID: 29447731). This variant has been identified in 17/265018 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 missense variant replaces arginine with cysteine at codon 177 of the MYBPC3 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with hypertrophic cardiomyopathy (PMID: 22555271, 30762279). One of these individuals carried a pathogenic truncation variant in the same gene (PMID: 22555271). This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 24503780, 24062880, 24503780, 27532257, 32746448, 32880476, 36178741). One of these individuals also carried a pathogenic variant in the MYH7 gene (PMID: 36178741). This variant has also been reported in an individual affected with non-compaction cardiomyopathy (PMID: 29447731). This variant has been identified in 17/265018 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.

Identified in patients with cardiomyopathy in published literature; however, several patients harbored pathogenic or likely pathogenic variants in other cardiomyopathy-related genes (PMID: 23054336, 24503780, 27532257, 29447731, 30762279, 32880476, 32746448, 36178741, 37652022, Rippert2023[article]); Identified in a family with a history of DCM and congenital heart abnormalities; however, the proband from this family and other affected relatives also harbored a missense variant in the VCL gene, and the most severely affected individuals harbored both the MYBPC3 and VCL variants (PMID: 24062880); 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: 21415409, 27532257, 30762279, 25637381, 23299917, 22555271, 28518168, 33782553, 32880476, 32746448, 36178741, 34097875, 24503780, 29447731, 23054336, 37652022, Rippert2023[article], 37937776, 24062880)