Submissions for variant NM_032578.4(MYPN):c.3763G>A (p.Val1255Met)

gnomAD frequency: 0.00006  dbSNP: rs750655311

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000222515	SCV000272187	uncertain significance	not specified	2016-03-18	criteria provided, single submitter	clinical testing	The p.Val1255Met variant in MYPN has not been previously reported in individuals with cardiomyopathy, but has been identified in 2/11564 of Latino chromosomes b y the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs750655311). Computational prediction tools and conservation analysis do not pr ovide strong support for or against an impact to the protein. In summary, the cl inical significance of the p.Val1255Met variant is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000463619	SCV000553461	uncertain significance	Dilated cardiomyopathy 1KK	2022-08-16	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1255 of the MYPN protein (p.Val1255Met). This variant is present in population databases (rs750655311, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with MYPN-related conditions. ClinVar contains an entry for this variant (Variation ID: 229036). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or 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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV001256744	SCV001433151	uncertain significance	Dilated cardiomyopathy 1A	2019-03-15	criteria provided, single submitter	clinical testing
GeneDx	RCV002272178	SCV002558069	uncertain significance	not provided	2022-07-15	criteria provided, single submitter	clinical testing	Reported in one Spanish patient with DCM (Pea-Pea et al., 2021); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32826072)
Ambry Genetics	RCV002347845	SCV002623379	uncertain significance	Cardiovascular phenotype	2024-06-04	criteria provided, single submitter	clinical testing	The p.V1255M variant (also known as c.3763G>A), located in coding exon 18 of the MYPN gene, results from a G to A substitution at nucleotide position 3763. The valine at codon 1255 is replaced by methionine, an amino acid with highly similar properties. This variant has been reported in dilated cardiomyopathy (DCM) cohorts (Mazzarotto F et al. Circulation, 2020 Feb;141:387-398; Peña-Peña ML et al. Med Clin (Barc), 2021 May;156:485-495). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000222515	SCV005726726	likely benign	not specified	2024-11-12	criteria provided, single submitter	clinical testing	Variant summary: MYPN c.3763G>A (p.Val1255Met) results in a conservative amino acid change located in the Immunoglobulin I-set domain (IPR013098) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251188 control chromosomes (gnomAD). The observed variant frequency is approximately 1.1- fold of the estimated maximal expected allele frequency for a pathogenic variant in MYPN causing Cardiomyopathy phenotype (5e-05). c.3763G>A has been reported in the literature in at least an individual affected with dilated cardiomyopathy (example: Pena-Pena_2021). This report, however, does not provide unequivocal conclusions about association of the variant with cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 32826072). ClinVar contains an entry for this variant (Variation ID: 229036). Based on the evidence outlined above, the variant was classified as likely benign.