ClinVar Miner

Submissions for variant NM_032578.3(MYPN):c.2864G>A (p.Arg955Gln) (rs199476414)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000024524 SCV000054743 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
GeneDx RCV000024524 SCV000236073 uncertain significance not provided 2017-05-30 criteria provided, single submitter clinical testing This variant is denoted p.Arg955Gln (CGG>CAG): c.2864 G>A in exon 13 of the MYPN gene (NM_032578.3). Mutations in the MYPN gene have been reported previously in association with familial cardiomyopathy (Duboscq-Bidot, L et al., 2008; Purevjav E at al., 2012; Meyer T et al., 2013). The prevalence of MYPN mutations in familial cardiomyopathy is currently unknown. The R955Q variant was identified in 2/348 individuals with DCM and 3/1020 control individuals (Purevjav E et al., 2012). Another missense variant in the same residue (R955W) has been reported in association with DCM; however, functional characterization of that substitution suggested that a nucleotide exchange in residue 955 appeared to be less critical for the cardiac function of myopalladin (Meyer T et al., 2013). Nevertheless, the R955Q variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R955Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved through mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense mutations in nearby residues (F954L, P961L) have been reported in association with DCM, supporting the functional importance of this region of the protein. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CARDIOMYOPATHY panel(s).
Invitae RCV000526341 SCV000659195 uncertain significance Dilated cardiomyopathy 1KK 2018-11-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 955 of the MYPN protein (p.Arg955Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs199476414, ExAC 0.009%) . This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 22286171). ClinVar contains an entry for this variant (Variation ID: 31831). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
Leiden Muscular Dystrophy (MYPN) RCV000024524 SCV000045828 not provided not provided 2012-04-27 no assertion provided curation
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000526341 SCV000732954 uncertain significance Dilated cardiomyopathy 1KK no assertion criteria provided clinical testing

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