rs118203981

Variant names:

• chr1-42738540-A-C
• rs118203981
• NM_148960.3:c.269T>G

Your query was ambiguous. Multiple possible variants found:

• chr1-42738540-A-C
• chr1-42738540-A-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_148960.3(CLDN19):​c.269T>G​(p.Leu90Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L90P) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CLDN19 NM_148960.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.32

Genes affected

CLDN19 (HGNC:2040): (claudin 19) The product of this gene belongs to the claudin family. It plays a major role in tight junction-specific obliteration of the intercellular space, through calcium-independent cell-adhesion activity. Defects in this gene are the cause of hypomagnesemia renal with ocular involvement (HOMGO). HOMGO is a progressive renal disease characterized by primary renal magnesium wasting with hypomagnesemia, hypercalciuria and nephrocalcinosis associated with severe ocular abnormalities such as bilateral chorioretinal scars, macular colobomata, significant myopia and nystagmus. Alternatively spliced transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jun 2010]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a chain Claudin-19 (size 223) in uniprot entity CLD19_HUMAN there are 14 pathogenic changes around while only 5 benign (74%) in NM_148960.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-42738540-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 1363.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.944
• PP5: Variant 1-42738540-A-C is Pathogenic according to our data. Variant chr1-42738540-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 548636.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLDN19	NM_148960.3	c.269T>G	p.Leu90Arg	missense_variant	Exon 2 of 5	ENST00000296387.6	NP_683763.2
CLDN19	NM_001185117.2	c.269T>G	p.Leu90Arg	missense_variant	Exon 2 of 3		NP_001172046.1
CLDN19	NM_001123395.2	c.269T>G	p.Leu90Arg	missense_variant	Exon 2 of 4		NP_001116867.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLDN19	ENST00000296387.6	c.269T>G	p.Leu90Arg	missense_variant	Exon 2 of 5	2	NM_148960.3	ENSP00000296387.1
CLDN19	ENST00000372539.3	c.269T>G	p.Leu90Arg	missense_variant	Exon 2 of 4	1		ENSP00000361617.3
CLDN19	ENST00000539749.5	c.269T>G	p.Leu90Arg	missense_variant	Exon 2 of 3	2		ENSP00000443229.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Renal hypomagnesemia 5 with ocular involvement Pathogenic:2

Jan 03, 2022

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Jul 10, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Aug 29, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;.;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.5	M;M;M
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-5.3	D;D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.94
MutPred		0.79		Gain of MoRF binding (P = 0.0078);Gain of MoRF binding (P = 0.0078);Gain of MoRF binding (P = 0.0078);
MVP		0.97
MPC		1.2
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.98
gMVP		0.94

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: rs118203981; hg19: chr1-43204211;