rs386833981

Variant names:

• chr13-77000517-T-G
• rs386833981
• NM_006493.4:c.625T>G

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_006493.4(CLN5):​c.625T>G​(p.Tyr209Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,724 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. Y209C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CLN5 NM_006493.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.91
• Publications: 8 publications found

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]

ENSG00000283208 (HGNC:):

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 Gene-Disease associations (from GenCC):

• intellectual disability, short stature, facial anomalies, and joint dislocations

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-77000518-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2627620.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.955
• PP5: Variant 13-77000517-T-G is Pathogenic according to our data. Variant chr13-77000517-T-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 56545.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
CLN5	NM_006493.4	c.625T>G	p.Tyr209Asp	missense_variant	Exon 4 of 4	ENST00000377453.9	NP_006484.2
CLN5	NM_001366624.2	c.*74T>G		3_prime_UTR_variant	Exon 5 of 5		NP_001353553.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLN5	ENST00000377453.9	c.625T>G	p.Tyr209Asp	missense_variant	Exon 4 of 4	1	NM_006493.4	ENSP00000366673.5
ENSG00000283208	ENST00000638147.2	c.565+4390T>G		intron_variant	Intron 3 of 4	5		ENSP00000490953.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461724 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727146

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111946

Other (OTH) AF: 0.00 AC: 0 AN: 60382

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neuronal ceroid lipofuscinosis 5 Pathogenic:3

-

Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 11, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 01, 2022

Solve-RD Consortium

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Variant confirmed as disease-causing by referring clinical team -

Neuronal ceroid lipofuscinosis Pathogenic:2

Mar 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 258 of the CLN5 protein (p.Tyr258Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal recessive neuronal ceroid lipofuscinosis (PMID: 17607606, 28542837). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 56545). 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%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

May 19, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CLN5 c.625T>G (p.Tyr209Asp) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant was absent in 251156 control chromosomes. c.625T>G has been observed in homozygous and compound heterozygous individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) (Simonati_2017). 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. The most pronounced variant effect results in loss of protein expression in fibroblasts derived from an individual homozygous for this variant (Simonati_2017). The following publication have been ascertained in the context of this evaluation (PMID: 28542837). ClinVar contains an entry for this variant (Variation ID: 56545). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D;D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T;T
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Uncertain	2.4	.;M
PhyloP100		7.9
PrimateAI	Uncertain	0.69	T
REVEL	Pathogenic	0.95
Polyphen		1.0	.;D
MutPred		0.81		.;Loss of sheet (P = 0.0025);
MVP		0.99
MPC		0.98
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.95
Mutation Taster		=10/90	disease causing (ClinVar)

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: rs386833981; hg19: chr13-77574652;