Submissions for variant NM_148960.3(CLDN19):c.59G>A (p.Gly20Asp)

gnomAD frequency: 0.00003  dbSNP: rs118203979

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000823362	SCV000964216	pathogenic	not provided	2025-01-06	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 20 of the CLDN19 protein (p.Gly20Asp). 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 missense change has been observed in individuals with familial hypomagnesemia with hypercalciuria and nephrocalcinosis (PMID: 17033971, 23301036, 25366522, 25410674, 27530400). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1361). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CLDN19 function (PMID: 17033971, 18188451). For these reasons, this variant has been classified as Pathogenic.
Molecular Biology Laboratory, Fundació Puigvert	RCV000001426	SCV001424990	likely pathogenic	Renal hypomagnesemia 5 with ocular involvement	2020-02-01	criteria provided, single submitter	research
Fulgent Genetics, Fulgent Genetics	RCV000001426	SCV001752656	pathogenic	Renal hypomagnesemia 5 with ocular involvement	2024-06-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000823362	SCV003915342	pathogenic	not provided	2022-10-05	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect on protein trafficking and/or assembly, impairing its function during renal tubular and retinal epithelial development (Konrad et al., 2006; Wang et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 18188451, Xu2017[abstract], 25366522, 30937396, 25317625, 17033971, 27530400, 22422540, 34425238, 31694170, 33532864, 25410674)
Neuberg Centre For Genomic Medicine, NCGM	RCV000001426	SCV004100582	pathogenic	Renal hypomagnesemia 5 with ocular involvement		criteria provided, single submitter	clinical testing
OMIM	RCV000001426	SCV000021576	pathogenic	Renal hypomagnesemia 5 with ocular involvement	2006-11-01	no assertion criteria provided	literature only
Molecular Genetics Laboratory, Biobizkaia Health Research Institute	RCV000001426	SCV004708188	pathogenic	Renal hypomagnesemia 5 with ocular involvement	2024-03-08	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003924792	SCV004741667	pathogenic	CLDN19-related disorder	2024-02-06	no assertion criteria provided	clinical testing	The CLDN19 c.59G>A variant is predicted to result in the amino acid substitution p.Gly20Asp. This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with familial hypomagnesemia, hypercalciuria, and nephrocalcinosis with ocular abnormalities (see for example, Figure 2, Konrad et al. 2006. PubMed ID: 17033971; Almeida et al. 2014. PubMed ID: 25317625; Table 1, Martin-Nuñez et al. 2014. PubMed ID: 25410674). This variant is reported in 0.045% of alleles in individuals of Latino descent in gnomAD. Functional studies suggest this variant impairs protein function (Figure 2, Hou et al. 2008. PubMed ID: 18188451; Figure 2, Wang et al. 2019. PubMed ID: 30937396). This variant is interpreted as pathogenic.