ClinVar Miner

Submissions for variant NM_000553.6(WRN):c.3259A>G (p.Lys1087Glu)

gnomAD frequency: 0.00028  dbSNP: rs374154973
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000232120 SCV000285555 likely benign Werner syndrome 2024-01-29 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000232120 SCV000897447 uncertain significance Werner syndrome 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV001356218 SCV002027837 uncertain significance not provided 2021-05-17 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
PreventionGenetics, part of Exact Sciences RCV003919924 SCV004734252 uncertain significance WRN-related condition 2023-10-18 criteria provided, single submitter clinical testing The WRN c.3259A>G variant is predicted to result in the amino acid substitution p.Lys1087Glu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.037% of alleles in individuals of European (Non-Finnish) descent in gnomAD, including one homozygous individual (http://gnomad.broadinstitute.org/variant/8-31000167-A-G) and has conflicting interpretations in ClinVar, ranging from uncertain significance to likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/238150/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001356218 SCV001551326 uncertain significance not provided no assertion criteria provided clinical testing The WRN p.Lys1087Glu variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs374154973) and ClinVar (classified as uncertain significance by Invitae and Fulgent Genetics for Werner syndrome). The variant was identified in control databases in 54 of 279522 chromosomes (1 homozygous) at a frequency of 0.0001932 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 47 of 128198 chromosomes (freq: 0.000367), African in 4 of 24796 chromosomes (freq: 0.000161), Latino in 2 of 34780 chromosomes (freq: 0.000058) and South Asian in 1 of 29552 chromosomes (freq: 0.000034), but was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), or Other populations. The p.Lys1087 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out 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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