rs386833694

chr16-28482161-G-Achr16-28482161-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001042432.2(CLN3):c.1000C>T(p.Arg334Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,512 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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. R334H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: CLN3 NM_001042432.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.92

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain 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 chr16-28482160-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56244.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 16-28482161-G-A is Pathogenic according to our data. Variant chr16-28482161-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-28482161-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLN3	NM_001042432.2	c.1000C>T	p.Arg334Cys	missense_variant	14/16	ENST00000636147.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLN3	ENST00000636147.2	c.1000C>T	p.Arg334Cys	missense_variant	14/16	1	NM_001042432.2	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249336 Hom.: 0 AF XY: 0.00000741 AC XY: 1 AN XY: 134876

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: 0.00

Gnomad NFE exome AF: 0.00000888

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461512 Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5 AN XY: 727044

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000594

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neuronal ceroid lipofuscinosis 3 Pathogenic:3

Likely pathogenic, no assertion criteria provided	literature only	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 31, 2023	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Oct 16, 2018	- -

Neuronal ceroid lipofuscinosis Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 21, 2019	Variant summary: CLN3 c.1000C>T (p.Arg334Cys) 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 was absent in 275064 control chromosomes (gnomAD). c.1000C>T has been reported in the literature in individuals affected with Juvenile Neuronal Ceroid-Lipofuscinosis (Juvenile Batten Disease). These data indicate that the variant may be associated with disease. The c.1000C>T variant has been reported in the literature in several individuals affected with Juvenile Neuronal Ceroid-Lipofuscinosis (Juvenile Batten Disease), indicating that the variant may be associated with disease. Additionally, a variant affecting the same codon c.1001G>A (p.R334H) was also observed in 4 families with classical JNCL phenotype, indicating residue 334 is likely critical for normal function of the CLN3 protein. The variant is located in the third lumenal region on the predicted lumenal face of a putative amphipathic helix, and all proteins mutated in this region were defective in function observed by a functional study (Haines_2009), suggesting this region has a significant effect on the protein function. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 21, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 334 of the CLN3 protein (p.Arg334Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with isolated retinitis pigmentosa and/or neuronal ceroid lipofuscinosis (PMID: 9311735, 17475770, 21990111, 25976102, 33507216, 33921607). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 56243). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CLN3 protein function. Experimental studies have shown that this missense change affects CLN3 function (PMID: 10924275, 11589014, 17475770, 19132115). This variant disrupts the p.Arg334 amino acid residue in CLN3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9311735, 20187884, 21499717, 21990111, 23539563). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;.;.;.;.;D;D;D;.;D;D;D;.;D;D;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.63	T
Polyphen		1.0	.;.;D;D;.;D;.;.;.;D;D;D;D;.;D;.;.
Vest4		0.95, 0.95, 0.88, 0.97, 0.89
MutPred		0.97		.;.;Loss of MoRF binding (P = 0.0031);Loss of MoRF binding (P = 0.0031);.;.;.;.;.;Loss of MoRF binding (P = 0.0031);.;.;.;.;.;.;.;
MVP		0.97
MPC		0.74
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.91
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs386833694; hg19: chr16-28493482;