Submissions for variant NM_000256.3(MYBPC3):c.667G>A (p.Glu223Lys)

gnomAD frequency: 0.00003  dbSNP: rs397516069

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035661	SCV000059312	uncertain significance	not specified	2015-03-30	criteria provided, single submitter	clinical testing	The p.Glu223Lys variant in MYBPC3 has been identified by our laboratory in 1 adu lt with HCM who also carried a pathogenic MYBPC3 variant on the other allele (in trans). This variant has been identified in 0.1% (11/8852) of Latino chromosome s by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbS NP rs397516069). Computational prediction tools and conservation analysis sugges t that the p.Glu223Lys variant may impact the protein, though this information i s not predictive enough to determine pathogenicity. In summary, the clinical sig nificance of the p.Glu223Lys variant is uncertain.
Invitae	RCV000225898	SCV000284251	uncertain significance	Hypertrophic cardiomyopathy	2023-07-03	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 42785). This missense change has been observed to co-occur in individuals with a different variant in MYBPC3 that has been determined to be pathogenic (PMID: 28771489), but the significance of this finding is unclear. This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 28771489). This variant is present in population databases (rs397516069, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 223 of the MYBPC3 protein (p.Glu223Lys).
Color Diagnostics, LLC DBA Color Health	RCV001180866	SCV001345907	uncertain significance	Cardiomyopathy	2022-11-07	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 223 of the MYBPC3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in an individual affected with hypertrophic cardiomyopathy, who also carried a pathogenic truncation variant in the same gene that could explain the observed phenotype (PMID: 28771489). This variant has been identified in 23/245622 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000035661	SCV004122783	uncertain significance	not specified	2023-10-12	criteria provided, single submitter	clinical testing	Variant summary: MYBPC3 c.667G>A (p.Glu223Lys) results in a conservative amino acid change located in the Immunoglobulin subtype (IPR003599) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.4e-05 in 245622 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MYBPC3 causing Cardiomyopathy (9.4e-05 vs 0.001), allowing no conclusion about variant significance. c.667G>A has been reported in the literature in an individual affected with Cardiomyopathy (Mademont-Soler_2017), also carrying a pathogenic variant (MYBPC3 c.2190del, p.K731Rfs*23), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 28771489). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003952403	SCV004776465	likely benign	MYBPC3-related condition	2020-04-01	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Clinical Genetics, Academic Medical Center	RCV001699020	SCV001918141	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001699020	SCV001952526	uncertain significance	not provided		no assertion criteria provided	clinical testing