Submissions for variant NM_000117.3(EMD):c.272A>G (p.Asn91Ser)

gnomAD frequency: 0.00018  dbSNP: rs137977232

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035105	SCV000058745	uncertain significance	not specified	2013-04-05	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Asn91Ser varian t in EMD has not been reported in the literature, but has been identified by our laboratory in 2 affected individuals, a male unspecified ethnicity with HCM and a female of Ashkenazi Jewish ancestry with DCM (LMM unpublished data). This var iant did not segregate with disease in the family with DCM. In addition, this va riant has been identified in 1/6725 European American chromosomes by the NHLBI E xome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs137977232). L astly, computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Asn91Ser variant may not impact the protein, though this information is not predictive enough to rule out patho genicity. In summary, the lack of segregation and presence in both HCM and DCM s uggest that this variant is more likely benign, but additional information is ne eded to fully assess the clinical significance of this variant.
GeneDx	RCV000035105	SCV000528908	likely benign	not specified	2017-04-28	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001085397	SCV000636282	benign	X-linked Emery-Dreifuss muscular dystrophy	2024-01-31	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000035105	SCV000707434	likely benign	not specified	2017-04-07	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000756071	SCV000883786	likely benign	not provided	2017-08-07	criteria provided, single submitter	clinical testing	The c.272A>G; p.Asn91Ser variant (rs137977232) has not been reported in the medical literature, nor has it been previously identified by our laboratory. This variant is listed in the Genome Aggregation Database (gnomAD) with a population frequency of 0.6 percent in the Ashkenazi Jewish population (identified on 43 out of 7,450 chromosomes, including17 hemizygotes), and has been reported to ClinVar (Variation ID: 42272). The asparagine at position 91 is moderately conserved considering 11 species (Alamut v2.9.0) and computational analyses of the effects of the p.Asn91Ser variant on protein structure and function provide conflicting results (SIFT: tolerated, MutationTaster: disease causing, PolyPhen-2: benign). Given the overabundance of hemizygotes in the population (21 total in gnomAD), the p.Asn91Ser is likely benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770588	SCV000902037	uncertain significance	Cardiomyopathy	2016-05-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002426545	SCV002741575	likely benign	Cardiovascular phenotype	2019-05-29	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000035105	SCV000280101	uncertain significance	not specified	2015-09-16	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Given the conflicting phenotype of the cases and the presence in unselected individuals, we consider this variant a variant of uncertain significance. We could find no published reports of the variant. It was reported online in 19 of 42,479 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of September 15th, 2015). The ExAC site notes that the variant is callable in <80% of subjects, which may indicate this is a low-quality site. Specifically, the variant was observed in 19 of 23,040 European individuals (MAF 0.04%). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease.