Submissions for variant NM_032578.4(MYPN):c.3833G>A (p.Arg1278Gln)

gnomAD frequency: 0.00052  dbSNP: rs142877365

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172081	SCV000054745	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000216203	SCV000272188	uncertain significance	not specified	2015-03-30	criteria provided, single submitter	clinical testing	The p.Arg1278Gln variant in MYPN has not been previously reported in individuals with cardiomyopathy, but has been identified in 46/66734 European chromosomes b y the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs142877365). 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.Arg1278Gln variant is uncertain.
Invitae	RCV000230154	SCV000291124	uncertain significance	Dilated cardiomyopathy 1KK	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1278 of the MYPN protein (p.Arg1278Gln). This variant is present in population databases (rs142877365, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. 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: 191759). 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 disruptive. 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.
Ambry Genetics	RCV000251155	SCV000318925	likely benign	Cardiovascular phenotype	2020-11-18	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000172081	SCV000583342	uncertain significance	not provided	2023-10-23	criteria provided, single submitter	clinical testing	Reported in one individual from a cohort of individuals not selected for cardiomyopathy, arrhythmia, or family history of sudden cardiac death, who underwent exome sequencing (PMID: 23861362); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23861362)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000216203	SCV000604432	uncertain significance	not specified	2017-02-16	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000172081	SCV001147947	uncertain significance	not provided	2022-09-01	criteria provided, single submitter	clinical testing	MYPN: PM2, BP4
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000230154	SCV001366450	uncertain significance	Dilated cardiomyopathy 1KK	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PP3,PP4.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470788	SCV002768584	uncertain significance	MYPN-related myopathy	2020-05-25	criteria provided, single submitter	clinical testing	A heterozygous missense variant was identified, NM_032578.3(MYPN):c.3833G>A in exon 20 of 20 of the MYPN gene. This substitution is predicted to create a minor amino acid change from arginine to glutamine at position 1278 of the protein, NP_115967.2(MYPN):p.(Arg1278Gln). The arginine at this position has high conservation (100 vertebrates, UCSC), but is not situated in a known functional domain. In silico software predicts this variant to be disease causing (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD population database at a frequency of 0.045% (127 heterozygotes, 0 homozygotes). Two alternative residue changes at the same location have been reported in the gnomAD database at a frequency of 0.0008% and 0.0012% respectively. It has been previously reported as a VUS in patients with a cardiovascular phenotype (ClinVar). Based on information available at the time of curation, this variant has been classified as a VARIANT of UNCERTAIN SIGNIFICANCE (VUS).
Fulgent Genetics, Fulgent Genetics	RCV002478552	SCV002782360	uncertain significance	Dilated cardiomyopathy 1KK; MYPN-related myopathy	2021-08-04	criteria provided, single submitter	clinical testing