rs139842473

chr16-28477620-G-Achr16-28477620-G-Cchr16-28477620-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001042432.2(CLN3):c.1213C>T(p.Arg405Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00017 in 1,613,866 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R405Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: CLN3 NM_001042432.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:13 U:1
• Conservation: PhyloP100: 3.48

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972
• PP5: Variant 16-28477620-G-A is Pathogenic according to our data. Variant chr16-28477620-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 418137.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=10, Likely_pathogenic=1}. Variant chr16-28477620-G-A is described in Lovd as [Pathogenic]. Variant chr16-28477620-G-A is described in Lovd as [Likely_pathogenic]. Variant chr16-28477620-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.1213C>T	p.Arg405Trp	missense_variant	16/16	ENST00000636147.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLN3	ENST00000636147.2	c.1213C>T	p.Arg405Trp	missense_variant	16/16	1	NM_001042432.2	P1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000719 AC: 18 AN: 250418 Hom.: 0 AF XY: 0.0000665 AC XY: 9 AN XY: 135432

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000974

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000180 AC: 263 AN: 1461714 Hom.: 0 Cov.: 31 AF XY: 0.000182 AC XY: 132 AN XY: 727148

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000222

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152152 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74316

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000199 Hom.: 0

Bravo AF: 0.0000982

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.000273

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:13 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Neuronal ceroid lipofuscinosis 3 Pathogenic:5 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	ame nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000418137, PMID:24154662, PS1_S). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 24154662, 29049447, PM3_M). Itwas co-segregated with Ceroid lipofuscinosis, neuronal, 3 in multiple affected family members with additional meioses (PMID: 24154662, PP1_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.873, 3CNET: 0.99, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000067, PM2_M). STherefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	research	Ocular Genomics Institute, Massachusetts Eye and Ear	Apr 08, 2021	The CLN3 c.1213C>T variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2, PP3, PP1-S, PM3-S. Based on this evidence we have classified this variant as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 02, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	May 16, 2019	This variant was identified as homozygous -

Retinitis pigmentosa Pathogenic:4

Likely pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -
Pathogenic, criteria provided, single submitter	research	Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel	Jul 24, 2023	Clinical significance based on ACMG v2.0 -
Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Apr 01, 2021	The p.Arg405Trp variant in CLN3 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PM2, PM3, PP1, PP5. Based on this evidence we have classified this variant as Likely pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	Sep 01, 2016	- -

Neuronal ceroid lipofuscinosis Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 405 of the CLN3 protein (p.Arg405Trp). This variant is present in population databases (rs139842473, gnomAD 0.01%). This missense change has been observed in individuals with retinitis pigmentosa (PMID: 24154662, 26766544, 28041643, 28559085). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 418137). 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%. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 06, 2021	Variant summary: CLN3 c.1213C>T (p.Arg405Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-05 in 250418 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in CLN3 causing Juvenile Neuronal Ceroid-Lipofuscinosis (Juvenile Batten Disease) (0.0014), allowing no conclusion about variant significance. The variant, c.1213C>T, has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with isolated (i.e. nonsyndromic) retinitis pigmentosa (e.g. Wang_2014, Weisschuh_2016, Haer-Wigman_2017, Smirnov_2021), as well as in at least two homozygous patients in whom the development of late neurological involvement was also reported, suggestive of Juvenile Neuronal Ceroid-Lipofuscinosis (JNCL; or Juvenile Batten Disease) (Kuper_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports that the variant was associated with increased lymphocyte vacuolization in patient-derived peripheral blood samples; however, the degree of vacuolization was less pronounced than in samples derived from patients with more severe, classical CLN3 disease phenotypes (Kuper_2017). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and cited the variant as Pathogenic (n=2), Likely pathogenic (n=3) or VUS (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 14, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32441891, 24154662, 26766544, 28542676, 28559085, 32581362, 36139381, 28041643, 31568712, 28224992, 33507216, 32685355, 32037395) -

Retinal dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Apr 24, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.47
Cadd	Pathogenic	34
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D;D;.;.;D;.;.;D;D;D;.;D;.;.
Eigen	Pathogenic	0.68
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.87	D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Pathogenic	3.5	H;H;.;.;.;.;.;.;H;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;N
PrimateAI	Uncertain	0.57	T
Polyphen		1.0	D;D;.;.;D;.;.;.;D;D;D;D;.;D
Vest4		0.60, 0.84, 0.80, 0.78, 0.88, 0.80
MVP		0.96
MPC		0.64
ClinPred		0.97	D
GERP RS		4.1
Varity_R		0.89
gMVP		0.88

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: rs139842473; hg19: chr16-28488941;