ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.41A>G (p.Lys14Arg)

gnomAD frequency: 0.00001  dbSNP: rs779049126
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000481305 SCV000565267 uncertain significance not provided 2017-03-16 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the MYBPC3 gene. Although the K14R variant has not been published as a pathogenic variant or as a benign variant to our knowledge, it has previously been identified in one other unrelated individual who underwent genetic testing for DCM at GeneDx. This variant was not observed in approximately 6,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position that is conserved across species. However, the K14R variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis is inconsistent in its predictions at to whether or not this variant alters protein structure/function. Furthermore, only one missense variant in a nearby residue (S18L) has been reported in the Human Gene Mutation Database in association with DCM (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Invitae RCV000629011 SCV000749921 uncertain significance Hypertrophic cardiomyopathy 2024-01-24 criteria provided, single submitter clinical testing This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 14 of the MYBPC3 protein (p.Lys14Arg). This variant is present in population databases (rs779049126, gnomAD 0.007%). 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: 418348). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Color Diagnostics, LLC DBA Color Health RCV001191588 SCV001359458 uncertain significance Cardiomyopathy 2023-11-27 criteria provided, single submitter clinical testing This missense variant replaces lysine with arginine at codon 14 of the MYBPC3 protein. Computational prediction indicates that this variant may have a neutral impact on 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 an individual affected with hypertrophic cardiomyopathy (PMID: 26914223). This variant has been identified in 2/233798 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.
Ambry Genetics RCV003298541 SCV004001262 uncertain significance Cardiovascular phenotype 2023-05-09 criteria provided, single submitter clinical testing The p.K14R variant (also known as c.41A>G), located in coding exon 2 of the MYBPC3 gene, results from an A to G substitution at nucleotide position 41. The lysine at codon 14 is replaced by arginine, an amino acid with highly similar properties. This alteration has been reported in a hypertrophic cardiomyopathy (HCM) cohort; however, clinical details were limited (Murphy SL et al. J Cardiovasc Transl Res, 2016 Apr;9:153-61). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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