ClinVar Miner

Submissions for variant NM_015404.4(WHRN):c.376G>A (p.Ala126Thr)

gnomAD frequency: 0.00001  dbSNP: rs1444564272
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001318082 SCV001508770 uncertain significance not provided 2022-01-07 criteria provided, single submitter clinical testing 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 1018742). This variant has not been reported in the literature in individuals affected with WHRN-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 126 of the WHRN protein (p.Ala126Thr).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV001449730 SCV001652996 likely benign not specified 2020-09-28 criteria provided, single submitter clinical testing The p.Ala126Thr variant in WHRN is classified as likely benign due to a lack of conservation across species. Four mammals (dolphin, killer whale, Cape elephant shrew, Cape golden mole) carry a threonine (Thr) at this position despite high nearby amino acid conservation. ACMG/AMP Criteria applied: BP4_Strong.

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