Submissions for variant NM_000256.3(MYBPC3):c.3097C>T (p.Arg1033Trp)

gnomAD frequency: 0.00002  dbSNP: rs748909815

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000489701	SCV000576673	uncertain significance	not provided	2022-09-27	criteria provided, single submitter	clinical testing	Reported in a Chinese individual with HCM who also harbored a second variant in the MYBPC3 gene (Zou et al., 2013); Reported in a Hispanic male with sudden death at 23 years old and findings of cardiac hypertrophy (Lin et al., 2017); 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: 23283745, 29247119)
Color Diagnostics, LLC DBA Color Health	RCV000772024	SCV000904980	uncertain significance	Cardiomyopathy	2023-09-22	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 1033 of the MYBPC3 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals with sudden unexplained death (PMID: 23283745, 29247119). One of these individuals were determined to have cardiac hypertrophy at autopsy (PMID: 29247119). This variant has been identified in 3/246342 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.
Blueprint Genetics	RCV000489701	SCV000927624	uncertain significance	not provided	2018-04-11	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001108212	SCV001265424	uncertain significance	Hypertrophic cardiomyopathy 4	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001108213	SCV001265425	uncertain significance	Left ventricular noncompaction 10	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001236686	SCV001409419	uncertain significance	Hypertrophic cardiomyopathy	2024-08-04	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1033 of the MYBPC3 protein (p.Arg1033Trp). This variant is present in population databases (rs748909815, gnomAD 0.007%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy or who suffered a sudden unexplained death (PMID: 23283745, 29247119, 35626289, 37652022; Invitae). ClinVar contains an entry for this variant (Variation ID: 426272). 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.Arg1033 amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been observed in individuals with MYBPC3-related conditions (PMID: 33658040; Invitae), which suggests that this may be a clinically significant amino acid residue. 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.
All of Us Research Program, National Institutes of Health	RCV001236686	SCV004836661	uncertain significance	Hypertrophic cardiomyopathy	2023-10-06	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 1033 of the MYBPC3 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals with sudden unexplained death (PMID: 23283745, 29247119). One of these individuals were determined to have cardiac hypertrophy at autopsy (PMID: 29247119). This variant has been identified in 3/246342 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001108212	SCV005398345	uncertain significance	Hypertrophic cardiomyopathy 4	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hypertrophic cardiomyopathy 4 (MIM#115197). (I) 0108 - This gene is associated with both recessive and dominant disease. Dominant inheritance is frequently reported in adult onset conditions, however recessive inheritance results in a more severe early onset phenotype (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (3 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (2 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated immunoglobulin (Ig)-like domain (NCBI, UniProt). (I) 0708 - Another missense variant comparable to the one identified in this case has conflicting previous evidence for pathogenicity. An alternate change to glutamine at the same residue has previously been reported in at least nine individuals with a relevant cardiac phenotype, predominantly for HCM. The variant has been described as likely pathogenic, however more frequently it is classified as a VUS (Atlas of Cardiac Genetic Variation, ClinVar, HGMD, LOVD, PMIDs: 20474083, 27532257, 28771489 & 29121657). (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. The variant has previously been reported in at least seven individuals with a relevant cardiac phenotype, predominantly for HCM. It has been described as pathogenic, however the majority of classifications are VUS (ClinVar, HGMD, PMIDs: 22958901, 23283745, 25132132, 28840316, 29247119 & 29687901). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign