X-50085987-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001127898.4(CLCN5):c.941C>T(p.Ser314Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000915 in 1,093,248 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S314S) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
• Consequence: CLCN5 NM_001127898.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 O:2
• Conservation: PhyloP100: 7.82

Genes affected

CLCN5 (HGNC:2023): (chloride voltage-gated channel 5) This gene encodes a member of the ClC family of chloride ion channels and ion transporters. The encoded protein is primarily localized to endosomal membranes and may function to facilitate albumin uptake by the renal proximal tubule. Mutations in this gene have been found in Dent disease and renal tubular disorders complicated by nephrolithiasis. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jan 2013]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973
• PP5: Variant X-50085987-C-T is Pathogenic according to our data. Variant chrX-50085987-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 11802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-50085987-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLCN5	NM_001127898.4	c.941C>T	p.Ser314Leu	missense_variant	10/15	ENST00000376091.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLCN5	ENST00000376091.8	c.941C>T	p.Ser314Leu	missense_variant	10/15	2	NM_001127898.4	P3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.15e-7 AC: 1 AN: 1093248 Hom.: 0 Cov.: 29 AF XY: 0.00000279 AC XY: 1 AN XY: 359028

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000218

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 18, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 18, 2020	Reported previously in multiple unrelated individuals with CLCN5-related disorders referred for genetic testing at GeneDx and in the published literature (Sekine et al. 2014; Wu et al. 2009); 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 (Lloyd et al., 1996; Grand et al., 2011; Tang et al., 2016); Not observed in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 22083641, 28580211, 8559248, 20804101, 21305656, 24081861, 19546591, 21955393, 27117801, 31672324, 31852738, 31674016, 9187673, 32393202) -

Hypophosphatemic rickets, X-linked recessive Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 1997	- -

CLCN5-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 23, 2023

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. -

X-linked recessive nephrolithiasis with renal failure;C1839874:Proteinuria, low molecular weight, with hypercalciuria and nephrocalcinosis;C1845168:Hypophosphatemic rickets, X-linked recessive;C1848336:Dent disease type 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 18, 2022

- -

Dent disease type 1 Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.64	D
BayesDel_noAF	Pathogenic	0.69
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.6	D;D;D;.;D;.
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D;D;.;D;.
Sift4G	Pathogenic	0.0010	D;D;D;.;D;.
Polyphen		1.0	D;D;D;D;D;.
Vest4		0.84
MutPred		0.86		.;.;Loss of disorder (P = 0.0204);Loss of disorder (P = 0.0204);Loss of disorder (P = 0.0204);.;
MVP		0.99
MPC		1.3
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.97
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs151340626; hg19: chrX-49850644;