rs104894386

chr13-76995077-G-Achr13-76995077-G-Cchr13-76995077-G-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2PM5PP3PP5_Very_Strong

The NM_006493.4(CLN5):c.188G>A(p.Arg63His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000093 in 1,613,730 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R63C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

CLN5
NM_006493.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 9.98

Variant links:

Genes affected

CLN5 (HGNC:2076): (CLN5 intracellular trafficking protein) This gene is one of eight which have been associated with neuronal ceroid lipofuscinoses (NCL). Also referred to as Batten disease, NCL comprises a class of autosomal recessive, neurodegenerative disorders affecting children. The genes responsible likely encode proteins involved in the degradation of post-translationally modified proteins in lysosomes. The primary defect in NCL disorders is thought to be associated with lysosomal storage function.[provided by RefSeq, Oct 2008]

CLN5 links:

FBXL3 (HGNC:13599): (F-box and leucine rich repeat protein 3) This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbls class and, in addition to an F-box, contains several tandem leucine-rich repeats and is localized in the nucleus. [provided by RefSeq, Jul 2008]

FBXL3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr13-76995076-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 190222.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=2}.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.802

PP5

Variant 13-76995077-G-A is Pathogenic according to our data. Variant chr13-76995077-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLN5	NM_006493.4 linkuse as main transcript	c.188G>A	p.Arg63His	missense_variant	2/4	ENST00000377453.9
CLN5	NM_001366624.2 linkuse as main transcript	c.188G>A	p.Arg63His	missense_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLN5	ENST00000377453.9 linkuse as main transcript	c.188G>A	p.Arg63His	missense_variant	2/4	1	NM_006493.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251186

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135764

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000889

AC:

AN:

1461568

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727078

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000989

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neuronal ceroid lipofuscinosis 5

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 22, 2005	- -

Neuronal ceroid lipofuscinosis

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 28, 2023	Variant summary: CLN5 c.188G>A (p.Arg63His), also referred to as p.Arg112His, results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251186 control chromosomes (gnomAD). c.188G>A has been reported in the literature in the homozygous state in two siblings and in at least one other unrelated individual affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) (e.g. Pineda-Trujilo_2005, Zhou_2018). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, indicating that the variant protein primarily localizes to the ER as opposed to the lysosome, however, it does not allow convincing conclusions about the variant effect (Schmiedt_2010). Other variants affecting the same amino acid (i.e. p.Arg63Cys, p.Arg63Pro) have been reported in association with Neuronal Ceroid-Lipofuscinosis in the HGMD database, suggesting Arg63 may be important for protein function, but this has yet to be determined conclusively. The following publications have been ascertained in the context of this evaluation (PMID: 15728307, 20052765, 30078242). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 09, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 15, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 112 of the CLN5 protein (p.Arg112His). This variant is present in population databases (rs104894386, gnomAD 0.003%). This missense change has been observed in individuals with juvenile onset neuronal ceroid lipofuscinosis (PMID: 15728307, 28542837, 30078242). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2567). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CLN5 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CLN5 function (PMID: 20052765). This variant disrupts the p.Arg112 amino acid residue in CLN5. Other variant(s) that disrupt this residue have been observed in individuals with CLN5-related conditions (PMID: 30078242), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 06, 2023

Published functional studies demonstrate a damaging effect as the R112H variant produces a protein unable to exit the endoplasmic reticulum (Schmiedt et al., 2010); Not observed at significant frequency in large population cohorts (gnomAD); 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: 21990111, 15728307, 33792748, 30264640, 28542837, 30078242, 32983231, 20052765) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.74

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.45

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Uncertain

0.51

D;T;D;T;T;.

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

D;.;D;.;.;.

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.80

D;D;D;D;D;D

MetaSVM

Pathogenic

0.84

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.69

Polyphen

1.0

.;.;D;.;.;.

MutPred

0.68

.;.;Gain of ubiquitination at K65 (P = 0.0483);.;.;.;

MVP

1.0

MPC

0.81

ClinPred

0.99

GERP RS

5.8

Varity_R

0.54

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over