ClinVar Miner

Submissions for variant NM_000553.6(WRN):c.1909C>T (p.Arg637Trp) (rs148286708)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000725735 SCV000339043 uncertain significance not provided 2016-01-27 criteria provided, single submitter clinical testing
Invitae RCV001080213 SCV000541486 benign Werner syndrome 2020-12-07 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001080213 SCV001320245 uncertain significance Werner syndrome 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
ITMI RCV000122277 SCV000086502 not provided not specified 2013-09-19 no assertion provided reference population
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000725735 SCV001552532 uncertain significance not provided no assertion criteria provided clinical testing The WRN p.Arg637Trp variant was identified in 1 of 18 Werner syndrome patients; the variant was identified as a compound heterozygous mutation in a male with Werner syndrome, osteoporosis and cancer (Uhrhammer_2006_PMID:16786514). The variant was identified in dbSNP (ID: rs148286708) and ClinVar (classified as uncertain significance by EGL Genetic Diagnotics and Invitae) but was not identified in Cosmic or LOVD 3.0. The variant was identified in control databases in 111 of 279850 chromosomes (0 homozygous) at a frequency of 0.0003966 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 7 of 10332 chromosomes (freq: 0.000678), European (non-Finnish) in 79 of 128100 chromosomes (freq: 0.000617), Other in 4 of 7152 chromosomes (freq: 0.000559), Latino in 17 of 35294 chromosomes (freq: 0.000482), South Asian in 3 of 30544 chromosomes (freq: 0.000098) and European (Finnish) in 1 of 23934 chromosomes (freq: 0.000042), but was not observed in the African or East Asian populations. The p.Arg637 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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.

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