Submissions for variant NM_000256.3(MYBPC3):c.3107G>A (p.Arg1036His)

gnomAD frequency: 0.00007  dbSNP: rs374255381

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158215	SCV000208150	uncertain significance	not specified	2016-07-06	criteria provided, single submitter	clinical testing	The R1036H variant has been reported in one patient with HCM (Lopes et al., 2015); however, familial segregation information, in vitro functional studies and additional clinical information was not included. The R1036H variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. However, the R1036H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, this substitution occurs at a position that is not conserved across species and where H1036 is the wild type in several species. Finally, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000554437	SCV000623583	uncertain significance	Hypertrophic cardiomyopathy	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1036 of the MYBPC3 protein (p.Arg1036His). This variant is present in population databases (rs374255381, gnomAD 0.01%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 25351510, 28356264). ClinVar contains an entry for this variant (Variation ID: 181000). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000158215	SCV000710913	likely benign	not specified	2017-01-31	criteria provided, single submitter	clinical testing	p.Arg1036His in exon 29 of MYBPC3: This variant is not expected to have clinical significance due to a lack of conservation across species, including mammals. O f note, 10 mammals have a histidine (His) at this position despite high nearby a mino acid conservation. This variant has also been identified in 1 individual wi th HCM (Lopes 2015) and 6/66506 of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs374255381).
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770326	SCV000901760	uncertain significance	Cardiomyopathy	2015-07-07	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000770326	SCV001344555	likely benign	Cardiomyopathy	2019-04-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002321660	SCV002608430	uncertain significance	Cardiovascular phenotype	2023-08-22	criteria provided, single submitter	clinical testing	The p.R1036H variant (also known as c.3107G>A), located in coding exon 29 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 3107. The arginine at codon 1036 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in hypertrophic cardiomyopathy (HCM) cohorts; however, clinical details were limited and other cardiac-related alterations were identified in some individuals (Lopes LR et al. Heart, 2015 Feb;101:294-301; Murphy SL et al. J Cardiovasc Transl Res. 2016 Apr;9(2):153-61 Gómez J et al. Circ Cardiovasc Genet, 2017 Apr;10). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001528580	SCV001740529	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001528580	SCV001928904	likely benign	not provided		no assertion criteria provided	clinical testing