ClinVar Miner

Submissions for variant NM_173477.5(USH1G):c.837C>G (p.Asp279Glu) (rs142486910)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000155318 SCV000205004 uncertain significance not specified 2015-09-08 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Asp279Glu var iant in USH1G has now been identified by our laboratory in 3 individuals with he aring loss; however, an alternate explanation of the hearing loss was identified in 1 family. This variant has also been identified in 0.1% (55/64670) of Europe an chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinsti tute.org; dbSNP rs142486910). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Co mputational prediction tools and conservation analysis suggest that the p.Asp279 Glu variant may not impact the protein, though this information is not predictiv e enough to rule out pathogenicity. In summary, while the clinical significance of the p.Asp279Glu variant is uncertain, these data suggest that it is more like ly to be benign.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000725682 SCV000338572 uncertain significance not provided 2016-01-25 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000999863 SCV000884835 uncertain significance Usher syndrome, type 1G 2018-11-07 criteria provided, single submitter clinical testing The p.Asp279Glu variant (rs142486910) has not been reported in the medical literature nor has it been previously identified in our laboratory; however, it is listed in the ClinVar database as a variant of uncertain significance (Variation ID: 178570). It is listed in the Genome Aggregation Database (gnomAD) browser with a frequency in Ashkenazi Jewish individuals of 0.56% (identified in 57 out of 10,112 chromosomes). The aspartic acid at codon 279 is not highly conserved (Alamut software v2.9), and several species including zebra finch and Xenopus tropical have a glutamic acid at this position suggesting this change is evolutionary tolerated. Furthermore, computational analyses suggest this variant does not have a significant effect on USH1G protein structure/function (SIFT: tolerated, PolyPhen2: benign, and Mutation Taster: polymorphism). However, based on the available information, the clinical significance of the p.Asp279Glu variant cannot be determined with certainty.
Invitae RCV000725682 SCV001054580 likely benign not provided 2020-11-20 criteria provided, single submitter clinical testing
GeneDx RCV000725682 SCV001864541 likely benign not provided 2020-10-13 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000725682 SCV001552135 uncertain significance not provided no assertion criteria provided clinical testing The USH1G p.Asp279Glu variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs142486910), LOVD 3.0 (classified as a VUS) and ClinVar (classified as a VUS by Laboratory for Molecular Medicine, ARUP Laboratories and EGL Genetics). EGL Genetics reported that they had identified the USH1G p.D279E variant in 3 individuals with hearing loss; but an alternate explanation of the hearing loss was identified in 1 family. The variant was identified in control databases in 168 of 279208 chromosomes at a frequency of 0.000602 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 60 of 10284 chromosomes (freq: 0.005834), Other in 8 of 7144 chromosomes (freq: 0.00112), European (non-Finnish) in 78 of 127154 chromosomes (freq: 0.000613), Latino in 18 of 35318 chromosomes (freq: 0.00051) and South Asian in 4 of 30564 chromosomes (freq: 0.000131), but was not observed in the African, East Asian or European (Finnish) populations. The variant occurs outside of the splicing consensus sequence and three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a greater than 10% difference in splicing. The p.Asp279 residue is conserved in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Clinical Genetics,Academic Medical Center RCV000725682 SCV001917821 uncertain significance not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000725682 SCV001971257 uncertain significance not provided no assertion criteria provided clinical testing

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