ClinVar Miner

Submissions for variant NM_000376.3(VDR):c.460C>T (p.Arg154Trp)

gnomAD frequency: 0.00001  dbSNP: rs746619116
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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 RCV001214658 SCV001386348 uncertain significance not provided 2021-08-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 154 of the VDR protein (p.Arg154Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs746619116, ExAC 0.001%). This missense change has been observed in individual(s) with clinical features of hereditary vitamin D resistant rickets (Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
3billion, Medical Genetics RCV002051923 SCV002318697 uncertain significance Vitamin D-dependent rickets type II with alopecia 2022-03-22 criteria provided, single submitter clinical testing The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000040). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.863>=0.6). A missense variant is a common mechanism. Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline.

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