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

gnomAD frequency: 0.00028  dbSNP: rs374154973

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000232120	SCV000285555	likely benign	Werner syndrome	2024-12-15	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
CeGaT Center for Human Genetics Tuebingen	RCV001356218	SCV005431937	likely benign	not provided	2024-10-01	criteria provided, single submitter	clinical testing	WRN: BP4
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.
PreventionGenetics, part of Exact Sciences	RCV003919924	SCV004734252	uncertain significance	WRN-related disorder	2023-10-18	no assertion criteria provided	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.