NM_006493.4:c.1028_1029delAT

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The NM_006493.4(CLN5):c.1028_1029delAT(p.Tyr343fs) 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 (★★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000037 ( 0 hom. )

Consequence

CLN5
NM_006493.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11O:1

Conservation

PhyloP100: 7.91

Publications

4 publications found

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:

ENSG00000283208 (HGNC:):

ENSG00000283208 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 Gene-Disease associations (from GenCC):

intellectual disability, short stature, facial anomalies, and joint dislocations
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

FBXL3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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 0.0455 CDS is truncated, and there are 3 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 VariationId is 2564.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 link	c.1028_1029delAT	p.Tyr343fs	frameshift_variant	Exon 4 of 4	ENST00000377453.9	NP_006484.2	O75503A0A024R644
CLN5	NM_001366624.2 link	c.477_478delAT		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 link	c.1028_1029delAT	p.Tyr343fs	frameshift_variant	Exon 4 of 4	1	NM_006493.4	ENSP00000366673.5		O75503
ENSG00000283208	ENST00000638147.2 link	c.565+4793_565+4794delAT		intron_variant	Intron 3 of 4	5		ENSP00000490953.2		A0A1B0GWJ7

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0000936

AC:

AN:

235034

AF XY:

0.000101

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 FIN exome

AF:

0.000805

Gnomad NFE exome

AF:

0.0000371

Gnomad OTH exome

AF:

0.000176

GnomAD4 exome

AF:

0.0000367

AC:

AN:

1444046

Hom.:

AF XY:

0.0000362

AC XY:

AN XY:

718400

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32406

American (AMR)

AF:

0.00

AC:

AN:

41708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25594

East Asian (EAS)

AF:

0.00

AC:

AN:

39582

South Asian (SAS)

AF:

0.00

AC:

AN:

83042

European-Finnish (FIN)

AF:

0.000713

AC:

AN:

51892

Middle Eastern (MID)

AF:

0.000176

AC:

AN:

5694

European-Non Finnish (NFE)

AF:

0.00000724

AC:

AN:

1104404

Other (OTH)

AF:

0.000117

AC:

AN:

59724

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41446

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.000660

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neuronal ceroid lipofuscinosis 5

Pathogenic:7Other:1

Mar 10, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 08, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 10, 2021

Genome-Nilou Lab

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jul 01, 1998

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Dec 03, 2018

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

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). -

Dec 19, 2019

Myriad Genetics, Inc.

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Neuronal ceroid lipofuscinosis

Pathogenic:3

Sep 12, 2022

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.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. -

Apr 27, 2021

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 16, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ClinVar contains an entry for this variant (Variation ID: 2564). 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. 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%). 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. -

not provided

Pathogenic:1

Mar 07, 2018

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Name

Calibrated prediction

Score

Prediction

PhyloP100

7.9

Mutation Taster

=6/194

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over