Submissions for variant NM_000256.3(MYBPC3):c.74G>A (p.Ser25Asn)

gnomAD frequency: 0.00021  dbSNP: rs371140684

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000151173	SCV000198991	uncertain significance	not specified	2013-09-18	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Ser25Asn varian t in MYBPC3 as not been previously reported in individuals with cardiomyopathy b ut has been identified in 0.1% (5/4232) of African American chromosomes by the N HLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs371140 684). Serine (Ser) at position 25 is not conserved in evolution with 2 species ( 1 mammal, 1 bird) carrying the variant amino acid, suggesting that this change m ay be tolerated. The change was also predicted to be benign using a computationa l tool clinically validated by our laboratory. This tool's benign prediction is estimated to be correct 89% of the time (Jordan 2011). Although this data suppor ts that the Ser25Asn variant may be benign, additional studies are needed to ful ly assess its clinical significance.
Illumina Laboratory Services, Illumina	RCV000402678	SCV000372419	uncertain significance	Dilated Cardiomyopathy, Dominant	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000314127	SCV000372420	uncertain significance	Hypertrophic cardiomyopathy	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000350432	SCV000372421	uncertain significance	Left ventricular noncompaction cardiomyopathy	2016-06-14	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000314127	SCV000623619	uncertain significance	Hypertrophic cardiomyopathy	2025-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 25 of the MYBPC3 protein (p.Ser25Asn). This variant is present in population databases (rs371140684, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with MYBPC3-related conditions. ClinVar contains an entry for this variant (Variation ID: 164159). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The asparagine 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170432	SCV001333011	likely benign	Cardiomyopathy	2021-10-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000151173	SCV001363320	uncertain significance	not specified	2024-11-26	criteria provided, single submitter	clinical testing	Variant summary: MYBPC3 c.74G>A (p.Ser25Asn) results in a conservative amino acid change located in the Immunoglobulin subtype 2 domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.2e-05 in 237812 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MYBPC3 causing Cardiomyopathy (4.2e-05 vs 0.001), allowing no conclusion about variant significance. c.74G>A has been reported in the literature in individuals affected with Cardiomyopathy. These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 164159). Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV002390324	SCV002672565	likely benign	Cardiovascular phenotype	2021-09-05	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Revvity Omics, Revvity	RCV003129791	SCV003817157	uncertain significance	not provided	2021-06-19	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224173	SCV003920225	uncertain significance	Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10	2021-03-30	criteria provided, single submitter	clinical testing	MYBPC3 NM_000256.3 exon 2 p.Ser25Asn (c.74G>A): This variant has not been reported in the literature but is present in 0.07% (17/22832) of African alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/11-47373008-C-T) and is present in ClinVar (Variation ID:164159). This variant amino acid (Asn) is present in several species including some mammals, and it is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
All of Us Research Program, National Institutes of Health	RCV000314127	SCV004845003	uncertain significance	Hypertrophic cardiomyopathy	2024-08-23	criteria provided, single submitter	clinical testing	This missense variant replaces serine with asparagine at codon 25 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 17/269206 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.
GeneDx	RCV003129791	SCV005396487	uncertain significance	not provided	2024-05-09	criteria provided, single submitter	clinical testing	Identified in a patient with HCM in published literature; this patient harbored additional cardiogenetic variants (PMID: 30847666); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24510615, 30847666)