Submissions for variant NM_000256.3(MYBPC3):c.2728C>A (p.Pro910Thr)

gnomAD frequency: 0.00021  dbSNP: rs397515985

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172008	SCV000050982	uncertain significance	Primary familial hypertrophic cardiomyopathy	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035525	SCV000059175	uncertain significance	not specified	2017-01-10	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx	RCV001703456	SCV000208103	likely benign	not provided	2020-04-14	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22361390, 21750094, 23861362, 18533079, 20215591, 21832052, 26914223, 27604170, 24111713, 21499742, 25351510, 21835320)
Invitae	RCV000557150	SCV000623569	uncertain significance	Hypertrophic cardiomyopathy	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 910 of the MYBPC3 protein (p.Pro910Thr). This variant is present in population databases (rs397515985, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with MYBPC3-related conditions (PMID: 20215591, 21499742, 21835320, 22361390, 24111713, 25351510, 26914223). ClinVar contains an entry for this variant (Variation ID: 42656). 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 tolerated. 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.
Ambry Genetics	RCV000617870	SCV000735984	likely benign	Cardiovascular phenotype	2022-05-27	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health	RCV000771802	SCV000904499	uncertain significance	Cardiomyopathy	2023-02-07	criteria provided, single submitter	clinical testing	This missense variant replaces proline with threonine at codon 910 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 21835320, 24111713, 26914223), dilated cardiomyopathy (PMID: 20215591), sudden cardiac death (PMID: 21499742), and sudden infant death syndrome (PMID: 22361390). One individual with hypertrophic cardiomyopathy had a different pathogenic variant in the same gene (PMID: 21835320). This variant has been identified in 25/172572 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.
Mendelics	RCV000988538	SCV001138293	uncertain significance	Hypertrophic cardiomyopathy 4	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001106086	SCV001263118	uncertain significance	Left ventricular noncompaction 10	2017-04-28	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.
Illumina Laboratory Services, Illumina	RCV000988538	SCV001263119	uncertain significance	Hypertrophic cardiomyopathy 4	2017-04-28	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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV001256919	SCV001433437	uncertain significance	Conduction disorder of the heart	2020-01-03	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000771802	SCV003838940	uncertain significance	Cardiomyopathy	2021-08-12	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001703456	SCV003916711	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	MYBPC3: BP4
Blueprint Genetics	RCV000157314	SCV000207049	uncertain significance	Brugada syndrome	2014-08-01	no assertion criteria provided	clinical testing