ClinVar Miner

Submissions for variant NM_000553.6(WRN):c.2328G>A (p.Met776Ile)

dbSNP: rs555281600
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001061106 SCV001225838 uncertain significance Werner syndrome 2024-02-19 criteria provided, single submitter clinical testing This sequence change replaces methionine with isoleucine at codon 776 of the WRN protein (p.Met776Ile). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and isoleucine. This variant is present in population databases (rs555281600, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with WRN-related conditions. ClinVar contains an entry for this variant (Variation ID: 855771). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV003243453 SCV003944234 uncertain significance Inborn genetic diseases 2023-06-06 criteria provided, single submitter clinical testing The c.2328G>A (p.M776I) alteration is located in exon 20 (coding exon 19) of the WRN gene. This alteration results from a G to A substitution at nucleotide position 2328, causing the methionine (M) at amino acid position 776 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences RCV004749596 SCV005352496 uncertain significance WRN-related disorder 2024-07-26 no assertion criteria provided clinical testing The WRN c.2328G>A variant is predicted to result in the amino acid substitution p.Met776Ile. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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