ClinVar Miner

Submissions for variant NM_148960.3(CLDN19):c.269T>G (p.Leu90Arg)

dbSNP: rs118203981
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
3billion, Medical Genetics RCV000662264 SCV002058560 likely pathogenic Renal hypomagnesemia 5 with ocular involvement 2022-01-03 criteria provided, single submitter clinical testing The variant was co-segregated with Hypomagnesemia 5, renal, with ocular involvement in multiple affected family members with additional meioses meeting (PMID: 27530400, PP1_M).The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 27530400, PM3_M). A different missense change at the same codon has been reported to be associated with CLDN19 related disorder (ClinVar ID: VCV000001363, PMID:17033971, PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.955, 3CNET: 0.839, PP3_P). A missense variant is a common mechanism associated with Hypomagnesemia 5 (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Labcorp Genetics (formerly Invitae), Labcorp RCV001868182 SCV002208373 pathogenic not provided 2021-08-29 criteria provided, single submitter clinical testing This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with arginine at codon 90 of the CLDN19 protein (p.Leu90Arg). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and arginine. This missense change has been observed in individuals with familial hypomagnesemia with hypercalciuria and nephrocalcinosis (PMID: 27530400). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 548636). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000662264 SCV000784592 pathogenic Renal hypomagnesemia 5 with ocular involvement 2018-07-10 no assertion criteria provided literature only

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