ClinVar Miner

Submissions for variant NM_032578.3(MYPN):c.2863C>T (p.Arg955Trp) (rs149887823)

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Total submissions: 7
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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 RCV000172574 SCV000054742 likely benign not provided 2013-06-24 criteria provided, single submitter research
GeneDx RCV000221588 SCV000236059 uncertain significance not specified 2016-12-15 criteria provided, single submitter clinical testing The R955W in the MYPN gene has been reported in a 44-year-old Caucasian male patient presenting with a reduced left-ventricular function, whose mother died of heart failure resulting from DCM, and was absent in 300 healthy controls (Meyer T et al., 2013). R955W is located in the alpha-actinin-binding region of myopalladin (Meyer T et al., 2013). The authors performed functional characterization of R955W by analyzing subcellular localization of myopalladin and alpha-actinin in cardiomyocytes by using indirect immunofluorescence microscopy on endomyocardial biopsy samples. They demonstate that the R955W carrier showed normal subcellular localization of myopalladin and alpha-actinin in cardiac myocytes, suggesting that a nucleotide exchange in codon 955 may not disrupt the cardiac function of myopalladin (Meyer T et al., 2013). The R955W variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The R955W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, the full clinical significance of this variant is uncertain (Landrum et al., 2014).
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000221588 SCV000272184 uncertain significance not specified 2015-07-07 criteria provided, single submitter clinical testing The p.Arg955Trp variant in MYPN was identified in 1 Caucasian adult with DCM (Me yer 2013). This variant has also been identified in 48/66700 of European chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs149887823). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Arg955Trp variant is uncertain.
Ambry Genetics RCV000619234 SCV000735246 uncertain significance Cardiovascular phenotype 2017-08-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000207001 SCV000776947 uncertain significance Dilated cardiomyopathy 1KK 2018-10-29 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 955 of the MYPN protein (p.Arg955Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs149887823, ExAC 0.07%). This variant has been reported in individuals affected with  left ventricular hypertrabeculation, left ventricular non-compaction, reduced left ventricular function and sudden cardiac death (PMID: 22892539, 28798025, 28087566). ClinVar contains an entry for this variant (Variation ID: 192126). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000172574 SCV000885812 uncertain significance not provided 2017-12-22 criteria provided, single submitter clinical testing The p.Arg955Trp (rs149887823) has been previously observed in four individuals included in a large cohort of cardiomyopathy patients, where it was classified as likely not pathogenic based on population frequency (Ng 2013). However this variant was observed in a 44-year old Caucasian male with reduced left ventricular function, whose mother had died of dilated cardiomyopathy (Meyer 2013). The same study demonstrated that this variant does not change sarcomeric distribution of MYPN by immunohistochemical staining when compared to WT. This variant is listed in the Genome Aggregation Database (gnomAD) with a frequency of 0.1 percent in the Ashkenazi Jewish population (identified on 13 out of 10,134 chromosomes), and has been reported to the ClinVar database (Variation ID: 192126). The arginine at position 955 is highly conserved considering 11 species (Alamut v2.10) and computational analyses of the p.Arg955Trp variant on protein structure and function indicate a deleterious effect (SIFT: damaging, MutationTaster: disease causing, PolyPhen-2: probably damaging). Altogether, there is not enough evidence to classify the p.Arg955Trp variant with certainty.
ClinVar Staff, National Center for Biotechnology Information (NCBI) RCV000207001 SCV000244011 uncertain significance Dilated cardiomyopathy 1KK 2013-06-27 no assertion criteria provided literature only

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