16-28482173-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_001042432.2(CLN3):c.988G>A(p.Val330Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000539 in 1,613,396 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. V330F) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000056 ( 0 hom. )

Consequence

CLN3
NM_001042432.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7U:1

Conservation

PhyloP100: 6.31

Variant links:

Genes affected

CLN3 (HGNC:2074): (CLN3 lysosomal/endosomal transmembrane protein, battenin) This gene encodes a protein that is involved in lysosomal function. Mutations in this, as well as other neuronal ceroid-lipofuscinosis (CLN) genes, cause neurodegenerative diseases commonly known as Batten disease or collectively known as neuronal ceroid lipofuscinoses (NCLs). Many alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2008]

CLN3 links:

ENSG00000261832 (HGNC:):

ENSG00000261832 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a topological_domain Lumenal (size 47) in uniprot entity CLN3_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_001042432.2

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-28482173-C-A is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.982

PP5

Variant 16-28482173-C-T is Pathogenic according to our data. Variant chr16-28482173-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 205095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-28482173-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLN3	NM_001042432.2 link	c.988G>A	p.Val330Ile	missense_variant	Exon 14 of 16	ENST00000636147.2	NP_001035897.1	Q13286-1A0A024QZB8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLN3	ENST00000636147.2 link	c.988G>A	p.Val330Ile	missense_variant	Exon 14 of 16	1	NM_001042432.2	ENSP00000490105.1		Q13286-1
ENSG00000261832	ENST00000637378.1 link	c.160G>A	p.Val54Ile	missense_variant	Exon 4 of 10	5		ENSP00000490831.1		A0A1B0GW90

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

151932

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.0000945

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000201

AC:

AN:

249164

Hom.:

AF XY:

0.0000223

AC XY:

AN XY:

134826

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000547

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000469

Gnomad NFE exome

AF:

0.0000267

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000561

AC:

AN:

1461464

Hom.:

Cov.:

AF XY:

0.0000578

AC XY:

AN XY:

727020

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000702

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000329

AC:

AN:

151932

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74178

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000945

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neuronal ceroid lipofuscinosis 3

Pathogenic:2Uncertain:1

Jan 02, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 10, 2021

Myriad Genetics, Inc.

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

NM_001042432.1(CLN3):c.988G>A(V330I) is a missense variant classified as a variant of uncertain significance in the context of CLN3-related neuronal ceroid lipofuscinosis. V330I has been observed in cases with relevant disease (PMID: 28542676). Functional assessments of this variant are not available in the literature. V330I has been observed in population frequency databases (gnomAD: EAS 0.01%). In summary, there is insufficient evidence to classify NM_001042432.1(CLN3):c.988G>A(V330I) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -

Aug 10, 2021

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Pathogenic:1

Nov 05, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.988G>A (p.V330I) alteration is located in exon 14 (coding exon 13) of the CLN3 gene. This alteration results from a G to A substitution at nucleotide position 988, causing the valine (V) at amino acid position 330 to be replaced by an isoleucine (I). Based on data from gnomAD, the A allele has an overall frequency of 0.003% (7/280370) total alleles studied. The highest observed frequency was 0.008% (2/24804) of European (Finnish) alleles. This variant has been identified in conjunction with other CLN3 variants in individuals with features consistent with CLN3-related disorders (Ku, 2017; external communication). This amino acid position is highly conserved in available vertebrate species. In an assay testing CLN3 function, this variant showed a functionally abnormal result (Scotto Rosato, 2022). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

not provided

Pathogenic:1

May 31, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate p.V330I causes protein subcellular mislocalization (Scotto et al., 2022); Reported in a patient with retinal disease who harbored a second CLN3 variant in unknown phase (Ku et al., 2017); Reported in a patient with retinitis pigmentosa (Carss et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22013180, 19132115, 32581362, 32441891, 35929194, 9311735, 30380624, 28041643, 28542676) -

Neuronal ceroid lipofuscinosis

Pathogenic:1

Jul 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 330 of the CLN3 protein (p.Val330Ile). This variant is present in population databases (rs386833744, gnomAD 0.008%). This missense change has been observed in individuals with retinitis pigmentosa and/or rod-cone dystrophy (PMID: 28542676; Invitae). ClinVar contains an entry for this variant (Variation ID: 205095). 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 CLN3 protein function with a positive predictive value of 80%. This variant disrupts the p.Val330 amino acid residue in CLN3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9311735, 19132115, 22013180). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Retinal dystrophy

Pathogenic:1

Jan 01, 2021

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa

Pathogenic:1

Jan 01, 2015

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.78

.;.;D;D;.;D;.;.;D;D;D;.;D;.;.;.;T

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D;.;.;.;.;D;D;D;.;D;D;D;.;D;D;D

M_CAP

Pathogenic

0.89

MetaRNN

Pathogenic

0.98

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.0

.;.;H;H;.;.;.;.;.;H;.;.;.;.;.;.;.

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.88

.;.;.;N;.;N;N;N;N;N;.;N;.;.;N;.;.

REVEL

Pathogenic

0.73

Sift

Pathogenic

0.0

.;.;.;D;.;D;D;D;T;D;.;D;.;.;D;.;.

Sift4G

Pathogenic

0.0

.;.;.;.;.;D;D;D;.;D;.;D;.;.;.;.;.

Polyphen

1.0, 1.0

.;.;D;D;.;D;.;.;.;D;D;D;D;.;D;.;.

Vest4

0.55, 0.58, 0.60, 0.57, 0.56

MutPred

0.89

.;.;Loss of methylation at R334 (P = 0.118);Loss of methylation at R334 (P = 0.118);.;.;.;.;.;Loss of methylation at R334 (P = 0.118);.;.;.;.;.;.;.;

MVP

0.90

MPC

0.57

ClinPred

0.99

GERP RS

5.4

Varity_R

0.75

gMVP

0.58

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