ClinVar Miner

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

gnomAD frequency: 0.00021  dbSNP: rs371140684
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Total submissions: 10
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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
Invitae RCV000314127 SCV000623619 uncertain significance Hypertrophic cardiomyopathy 2023-12-11 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). 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 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 2019-10-29 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 expected for a pathogenic variant in MYBPC3 causing Cardiomyopathy (4.2e-05 vs 0.001), allowing no conclusion about variant significance. c.74G>A has not been reported in the literature in individuals affected with Cardiomyopathy nor has experimental evidence demonstrating an impact on protein function been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. 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: 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 Omics 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.

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