Submissions for variant NM_000256.3(MYBPC3):c.1003C>T (p.Arg335Cys)

gnomAD frequency: 0.00001  dbSNP: rs730880630

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158326	SCV000208261	uncertain significance	not provided	2022-12-02	criteria provided, single submitter	clinical testing	Reported in association with HCM, although no clinical information or segregation data was provided (Cecconi et al., 2016); Reported in an infant with sudden cardiac death in his sleep at one year of age who was found to have an interventricular septum thickness of 7 mm on autopsy (Bagnall et al., 2016); 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: 27332903, 27600940)
Invitae	RCV000200384	SCV000254434	uncertain significance	Hypertrophic cardiomyopathy	2024-01-14	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 335 of the MYBPC3 protein (p.Arg335Cys). This variant is present in population databases (rs730880630, gnomAD 0.01%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy or sudden unexplained death (PMID: 27332903, 27600940, 28356264). ClinVar contains an entry for this variant (Variation ID: 181055). 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.
Illumina Laboratory Services, Illumina	RCV000334105	SCV000372372	likely benign	Left ventricular noncompaction 10	2018-01-13	criteria provided, single submitter	clinical testing	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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina	RCV001093999	SCV000372373	uncertain significance	Hypertrophic cardiomyopathy 4	2018-01-13	criteria provided, single submitter	clinical testing	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.
Ambry Genetics	RCV000620005	SCV000737376	uncertain significance	Cardiovascular phenotype	2016-11-01	criteria provided, single submitter	clinical testing	The p.R335C variant (also known as c.1003C>T), located in coding exon 12 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 1003. The arginine at codon 335 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was identified in a case of unexplained sudden cardiac death in a one year old male (Bagnall RD et al. N. Engl. J. Med., 2016 Jun;374:2441-52). Based on data from ExAC, the T allele has an overall frequency of <0.01% (2/94634). This amino acid position is highly conserved through mammals but not in all 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 variant remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV001189185	SCV001356420	uncertain significance	Cardiomyopathy	2023-11-27	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 335 of the MYBPC3 protein. Computational prediction tool indicates that this variant may have 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 two individuals affected with hypertrophic cardiomyopathy (PMID: 27600940, 28356264) and one individual with unexplained sudden cardiac death (PMID: 27332903). This variant has been identified in 7/247608 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.