ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.74G>A (p.Ser25Asn) (rs371140684)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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 Clinical Services Laboratory,Illumina RCV000402678 SCV000372419 uncertain significance Dilated Cardiomyopathy, Dominant 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000314127 SCV000372420 uncertain significance Hypertrophic cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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 2018-11-09 criteria provided, single submitter clinical testing This sequence change replaces serine with asparagine at codon 25 of the MYBPC3 protein (p.Ser25Asn). The serine residue is highly conserved and there is a small physicochemical difference between serine and asparagine. This variant is present in population databases (rs371140684, ExAC 0.08%) but has not been reported in the literature in individuals with a MYBPC3-related disease. ClinVar contains an entry for this variant (Variation ID: 164159). A computational algorithm designed to assess the pathogenicity of variants in MYBPC3 with regard to hypertrophic cardiomyopathy predicted this sequence change to be deleterious. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). The asparagine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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