Submissions for variant NM_001127898.4(CLCN5):c.941C>T (p.Ser314Leu)

dbSNP: rs151340626

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000485318	SCV000564885	pathogenic	not provided	2024-08-30	criteria provided, single submitter	clinical testing	Reported previously in multiple unrelated individuals with CLCN5-related disorders referred for genetic testing at GeneDx and in the published literature (PMID: 24081861, 19546591); Published functional and expression studies of the S244L variant show that its presence reduces the current of the CLCN5 chloride channel and significantly impairs CLCN5 transport function (PMID: 27117801, 8559248, 21305656); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; 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: 22083641, 36646056, 28580211, 8559248, 20804101, 21305656, 19546591, 21955393, 31672324, 31852738, 9187673, 32393202, 33852231, 31328266, 38002082, 38233994, 24081861, 27117801, 31674016)
Fulgent Genetics, Fulgent Genetics	RCV002482856	SCV002778776	pathogenic	Dent disease type 1; Hypophosphatemic rickets, X-linked recessive; X-linked recessive nephrolithiasis with renal failure; Proteinuria, low molecular weight, with hypercalciuria and nephrocalcinosis	2022-04-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000485318	SCV003522363	pathogenic	not provided	2024-05-02	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 244 of the CLCN5 protein (p.Ser244Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Dent disease (PMID: 19546591, 24081861, 27117801, 28580211, 31672324). ClinVar contains an entry for this variant (Variation ID: 11802). 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 CLCN5 function (PMID: 8559248, 27117801). For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003398487	SCV004120004	pathogenic	CLCN5-related disorder	2023-08-23	criteria provided, single submitter	clinical testing	The CLCN5 c.731C>T variant is predicted to result in the amino acid substitution p.Ser244Leu. This variant was reported in many individuals with Dent disease (Tang et al. 2016. PubMed ID: 27117801; Hureaux et al. 2019. PubMed ID: 31672324; Sekine et al. 2013. PubMed ID: 24081861), and was confirmed de novo in one Dent disease patient (Ye et al. 2020. PubMed ID: 31674016). This variant was also reported in two families with x-linked recessive hypophosphatemic rickets (Lloyd et al. 1996. PubMed ID: 8559248; Oudet et al. 1997. PubMed ID: 9187673). Experimental studies suggest this variant impacts protein function (Grand et al. 2011. PubMed ID: 21305656; Lourdel et al. 2011. PubMed ID: 22083641). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.
OMIM	RCV000012570	SCV000032804	pathogenic	Hypophosphatemic rickets, X-linked recessive	1997-06-01	no assertion criteria provided	literature only
GeneReviews	RCV000012570	SCV000055644	not provided	Hypophosphatemic rickets, X-linked recessive		no assertion provided	literature only
GeneReviews	RCV000192274	SCV000243782	not provided	Dent disease type 1		no assertion provided	literature only