rs145591298

Variant names:

• chr1-42735969-C-G
• rs145591298
• NM_148960.3:c.535G>C

Your query was ambiguous. Multiple possible variants found:

• chr1-42735969-C-G
• chr1-42735969-C-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2 PM5 PP3_Strong PP5_Moderate

The NM_148960.3(CLDN19):​c.535G>C​(p.Gly179Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. G179S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CLDN19 NM_148960.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.58
• Publications: 0 publications found

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]

CLDN19 Gene-Disease associations (from GenCC):

• renal hypomagnesemia 5 with ocular involvement

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-42735969-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 548672.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 1-42735969-C-G is Pathogenic according to our data. Variant chr1-42735969-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3242162.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLDN19	NM_148960.3	c.535G>C	p.Gly179Arg	missense_variant	Exon 4 of 5	ENST00000296387.6	NP_683763.2
CLDN19	NM_001123395.2	c.535G>C	p.Gly179Arg	missense_variant	Exon 4 of 4		NP_001116867.1
CLDN19	NM_001185117.2	c.450G>C	p.Ala150Ala	synonymous_variant	Exon 3 of 3		NP_001172046.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLDN19	ENST00000296387.6	c.535G>C	p.Gly179Arg	missense_variant	Exon 4 of 5	2	NM_148960.3	ENSP00000296387.1
CLDN19	ENST00000372539.3	c.535G>C	p.Gly179Arg	missense_variant	Exon 4 of 4	1		ENSP00000361617.3
CLDN19	ENST00000539749.5	c.450G>C	p.Ala150Ala	synonymous_variant	Exon 3 of 3	2		ENSP00000443229.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Renal hypomagnesemia 5 with ocular involvement Pathogenic:1

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense c.535G>C (p.Gly179Arg) variant in the CLDN19 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. A different amino acid change (p.Gly179Ser) is reported at the same position as a known pathogenic variant (Cogal et al., 2022). This variant is absent in gnomAD Exomes. The amino acid Glycine at position 179 is changed to an Arginine changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen - Damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The amino acid change p.Gly179Arg in CLDN19 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. As different amino acid change (p.Gly179Ser) is reported at the same position as a known pathogenic variant (Cogal et al., 2022) suggesting it is an important residue, however further functional evidence required to prove pathogenicity. For these reasons, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.87	D;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
PhyloP100		5.6
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-7.3	D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.98
MutPred		0.91		Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);
MVP		0.97
MPC		1.1
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.97
gMVP		0.96
Mutation Taster		=24/76	disease causing

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

Other links and lift over

dbSNP: rs145591298; hg19: chr1-43201640;