rs386833969

chr13-77000917-CAT-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_006493.4(CLN5):c.1028_1029del(p.Tyr343Ter) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000376 in 1,596,238 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T342T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000037 (0 hom.)
• Consequence: CLN5 NM_006493.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9 O:1
• Conservation: PhyloP100: 7.91

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]

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0474 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-77000917-CAT-C is Pathogenic according to our data. Variant chr13-77000917-CAT-C is described in ClinVar as [Pathogenic]. Clinvar id is 2564.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	c.1028_1029del	p.Tyr343Ter	frameshift_variant	4/4	ENST00000377453.9
CLN5	NM_001366624.2	c.*477_*478del		3_prime_UTR_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLN5	ENST00000377453.9	c.1028_1029del	p.Tyr343Ter	frameshift_variant	4/4	1	NM_006493.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000936 AC: 22 AN: 235034 Hom.: 0 AF XY: 0.000101 AC XY: 13 AN XY: 128136

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: 0.00

Gnomad FIN exome AF: 0.000805

Gnomad NFE exome AF: 0.0000371

Gnomad OTH exome AF: 0.000176

GnomAD4 exome AF: 0.0000367 AC: 53 AN: 1444046 Hom.: 0 AF XY: 0.0000362 AC XY: 26 AN XY: 718400

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: 0.000713

Gnomad4 NFE exome AF: 0.00000724

Gnomad4 OTH exome AF: 0.000117

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74360

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000660

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neuronal ceroid lipofuscinosis 5 Pathogenic:5 Other:1

Pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Dec 03, 2018	The homozygous p.Tyr392Ter variant in CLN5 was identified by our study in two siblings with Neuronal Ceroid Lipofuscinosis. This variant has been identified in 0.08321% (21/25238) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs762340626). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant is seen in a greater frequency in 18 affected Finnish individuals than in the general population (PMID: 9662406). The variant is believed to be a Finnish founder variant. In vitro functional studies provide some evidence that the p.Tyr392Ter variant may impact protein function by removing a N-glycosylation site and localization to the endoplasmic reticulum instead of the lysosomes (PMID: 24058541, 20052765). However, these types of assays may not accurately represent biological function. This nonsense variant leads to a premature termination codon at position 392. This alteration occurs within the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Loss of function of the CLN5 gene is an established disease mechanism in autosomal recessive Neuronal Ceroid Lipofuscinosis. In summary, the p.Tyr392Ter variant is pathogenic. ACMG/AMP Criteria applied: PM2, PS4, PS3, PVS1_Moderate (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 19, 2019	NM_006493.2(CLN5):c.1175_1176delAT(Y392*) is classified as pathogenic in the context of CLN5-related neuronal ceroid lipofuscinosis. Sources cited for classification include the following: PMID 9662406, 10953198, 12134079, 20052765, 24038957 and 12134079. Classification of NM_006493.2(CLN5):c.1175_1176delAT(Y392*) is based on the following criteria: The variant causes a premature termination codon that is not expected to be targeted by nonsense-mediated mRNA decay; however, literature evidence strongly supports pathogenicity. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, no assertion criteria provided	literature only	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	-	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 1998	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

Neuronal ceroid lipofuscinosis Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 16, 2023	This sequence change creates a premature translational stop signal (p.Tyr392*) in the CLN5 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 16 amino acid(s) of the CLN5 protein. For these reasons, this variant has been classified as Pathogenic. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CLN5 function (PMID: 11971870, 12134079, 20052765, 24038957, 24058541). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 2564). This premature translational stop signal has been observed in individual(s) with Finnish variant late infantile neuronal ceroid lipofuscinosis (PMID: 9662406). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs762340626, gnomAD 0.08%). -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 27, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 12, 2022	Variant summary: CLN5 c.1028_1029delAT (p.Tyr343X)(legacy name: c.1175_1176delAT, p.Tyr392X) is located in the last exon and results in a premature termination codon, which is not predicted to cause nonsense mediated decay, but is predicted to result in a truncation of the encoded protein, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 9.4e-05 in 235034 control chromosomes (gnomAD). c.1028_1029delAT has been reported in the literature as a biallelic genotype in multiple individuals of Finnish ancestry affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) and has been identified as a founder mutation within this population (e.g. Savukoski_1998, Holmberg_2000). These data indicate that the variant is very likely to be associated with disease. Experimental studies have shown that the variant results in a protein that is retained in the endoplasmic reticulum as opposed to localizing within lysosomes, suggesting it has a negative impact on protein function (e.g. Schmiedt_2010, Moharir_2013). Six submitters have provided assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 07, 2018

The c.1175_1176delAT pathogenic variant in the CLN5 gene has been reported multiple times previously in association with vLINCL and is considered to be a Finnish founder mutation (Savukoski et al., 1998). Functional studies suggest that the c.1175_1176delAT variant results in an unstable protein which is unable to enter the lysosome (Schmiedt et al., 2010; Moharir et al., 2013). The deletion causes a frameshift starting with codon Tyrosine 392 and changes this amino acid to a premature Stop codon, denoted p.Tyr392Ter. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.1175_1176delAT variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). -

Computational scores

Source: dbNSFP v4.3

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: rs386833969; hg19: chr13-77575052;