Submissions for variant NM_000256.3(MYBPC3):c.3064C>T (p.Arg1022Cys)

gnomAD frequency: 0.00002  dbSNP: rs397515999

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035553	SCV000059203	uncertain significance	not specified	2019-08-29	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg1022Cys variant in MYBPC3 has been identified in at least 7 individuals with HCM (Berge 2014, Bos 2014, Walsh 2017, Latif 2019, LMM data). It has also been identified in 2/24174 African chromosomes by gnomAD (http://gnomad.broadinstitute.org) and reported in ClinVar (Variation ID#42680). Computational tools suggest that this variant may impact protein function; however, this information is not predictive enough to determine pathogenicity. In addition, two other variants involving this codon, p.Arg1022His and p.Arg1022Pro, have been identified in individuals with HCM, suggesting that changes at this position may not be tolerated. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Arg1022Cys variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PP3, PS4_Moderate, PM5_Supporting.
GeneDx	RCV000766736	SCV000520819	uncertain significance	not provided	2023-05-17	criteria provided, single submitter	clinical testing	Reported in individuals with HCM, though detailed patient and family data were not provided (Berge et al., 2014; Bos et al., 2014; Walsh et al., 2017; Stava et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); 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: 22958901, 27532257, 24793961, 24111713, 33782553, 35653365)
Ambry Genetics	RCV000619067	SCV000740213	uncertain significance	Cardiovascular phenotype	2023-08-07	criteria provided, single submitter	clinical testing	The p.R1022C variant (also known as c.3064C>T), located in coding exon 29 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 3064. The arginine at codon 1022 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been detected in hypertrophic cardiomyopathy cohorts (HCM) and in cohorts referred for HCM genetic testing; however, clinical details were limited (Berge KE et al. Clin Genet. 2014;86:355-60; Bos JM et al. Mayo Clin Proc. 2014;89:727-37; Walsh R et al. Genet Med. 2017;19:192-203). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770328	SCV000901762	uncertain significance	Cardiomyopathy	2015-07-23	criteria provided, single submitter	clinical testing
Invitae	RCV000810358	SCV000950554	pathogenic	Hypertrophic cardiomyopathy	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1022 of the MYBPC3 protein (p.Arg1022Cys). 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 individuals with hypertrophic cardiomyopathy (PMID: 24111713, 24793961, 27532257, 33782553; Invitae). ClinVar contains an entry for this variant (Variation ID: 42680). 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. This variant disrupts the p.Arg1022 amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16335287, 20433692, 23396983, 28771489). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000770328	SCV001349202	likely pathogenic	Cardiomyopathy	2023-11-08	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 1022 in the Ig-like domain C8 of the MYBPC3 protein. Computational prediction suggests that this variant may have 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 over 10 individuals affected with hypertrophic cardiomyopathy (PMID: 24111713, 24793961, 27532257, 30790116, 35653365, 36788754; ClinVar SCV000950554.2). This variant has been identified in 3/278246 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
AiLife Diagnostics, AiLife Diagnostics	RCV000766736	SCV002501065	uncertain significance	not provided	2022-02-16	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002496535	SCV002781677	uncertain significance	Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10	2021-10-25	criteria provided, single submitter	clinical testing
3billion	RCV003152672	SCV003841730	likely pathogenic	Hypertrophic cardiomyopathy 4	2023-02-23	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.89; 3Cnet: 0.24). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with MYBPC3 related disorder (PMID: 24111713, 24793961, 27532257, 30790116). A different missense change at the same codon (p.Arg1022Pro) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000042682). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.