Submissions for variant NM_032578.4(MYPN):c.259C>G (p.Pro87Ala)

gnomAD frequency: 0.00010  dbSNP: rs376945733

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000694883	SCV000823349	uncertain significance	Dilated cardiomyopathy 1KK	2022-08-16	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 87 of the MYPN protein (p.Pro87Ala). This variant is present in population databases (rs376945733, gnomAD 0.04%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 31568572). ClinVar contains an entry for this variant (Variation ID: 573255). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.
Klaassen Lab, Charite University Medicine Berlin	RCV000853143	SCV000995856	uncertain significance	Primary dilated cardiomyopathy	2019-07-03	criteria provided, single submitter	research
Mayo Clinic Laboratories, Mayo Clinic	RCV001509386	SCV001716065	uncertain significance	not provided	2021-02-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002424651	SCV002744050	uncertain significance	Cardiovascular phenotype	2023-01-25	criteria provided, single submitter	clinical testing	The p.P87A variant (also known as c.259C>G), located in coding exon 1 of the MYPN gene, results from a C to G substitution at nucleotide position 259. The proline at codon 87 is replaced by alanine, an amino acid with highly similar properties. This variant has been detected in individuals with dilated cardiomyopathy; however, details were limited (Kühnisch J et al. Clin Genet, 2019 12;96:549-559; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002485681	SCV002790795	uncertain significance	Dilated cardiomyopathy 1KK; MYPN-related myopathy	2022-02-09	criteria provided, single submitter	clinical testing
GeneDx	RCV001509386	SCV005626542	uncertain significance	not provided	2024-07-07	criteria provided, single submitter	clinical testing	Identified in patients with DCM in published literature, including one pediatric patient (PMID: 31568572, 30847666); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31568572, 30847666)
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001509386	SCV001741903	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001509386	SCV001966522	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003953239	SCV004781263	uncertain significance	MYPN-related disorder	2023-12-20	no assertion criteria provided	clinical testing	The MYPN c.259C>G variant is predicted to result in the amino acid substitution p.Pro87Ala. This variant was reported as a variant of uncertain significance in individuals with dilated cardiomyopathy (online supplementary file 2, van Lint et al. 2019. PubMed ID: 30847666; Table S4, Kühnisch et al. 2019. PubMed ID: 31568572). This variant is reported in 0.040% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.