Submissions for variant NM_000553.6(WRN):c.2735T>G (p.Ile912Ser)

gnomAD frequency: 0.00005  dbSNP: rs11574323

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000229443	SCV000285543	likely benign	Werner syndrome	2024-01-24	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000229443	SCV000473338	uncertain significance	Werner syndrome	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV001357192	SCV001801299	likely benign	not provided	2018-08-20	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000229443	SCV003823795	uncertain significance	Werner syndrome	2022-06-24	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001357192	SCV004184347	likely benign	not provided	2023-11-01	criteria provided, single submitter	clinical testing	WRN: BP4, BS2
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357192	SCV001552578	likely benign	not provided		no assertion criteria provided	clinical testing	The WRN p.I912S variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs11574323) and ClinVar (classified as uncertain significance by Illumina and as likely benign by Invitae). The variant was identified in control databases in 122 of 267578 chromosomes (3 homozygous) at a frequency of 0.0004559 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: South Asian in 99 of 30486 chromosomes (freq: 0.003247), Ashkenazi Jewish in 7 of 9846 chromosomes (freq: 0.000711), Other in 1 of 6662 chromosomes (freq: 0.00015), European (non-Finnish) in 13 of 117852 chromosomes (freq: 0.00011), European (Finnish) in 1 of 25098 chromosomes (freq: 0.00004) and Latino in 1 of 35006 chromosomes (freq: 0.000029), but was not observed in the African or East Asian populations. The p.I912 residue is not 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.