ClinVar Miner

Submissions for variant NM_000117.2(EMD):c.272A>G (p.Asn91Ser) (rs137977232)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000035105 SCV000707434 likely benign not specified 2017-04-07 criteria provided, single submitter clinical testing
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.
Invitae RCV000549970 SCV000636282 benign Emery-Dreifuss muscular dystrophy 1, X-linked 2017-12-06 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare 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.
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.

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