NM_001042432.2(CLN3):c.175G>A (p.Ala59Thr) AND Neuronal ceroid lipofuscinosis

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Nov 3, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001222663.9

Allele description [Variation Report for NM_001042432.2(CLN3):c.175G>A (p.Ala59Thr)]

NM_001042432.2(CLN3):c.175G>A (p.Ala59Thr)

Gene:

CLN3:CLN3 lysosomal/endosomal transmembrane protein, battenin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16p12.1

Genomic location:

Preferred name:

NM_001042432.2(CLN3):c.175G>A (p.Ala59Thr)

HGVS:

NC_000016.10:g.28489337C>T
NG_008654.2:g.7966G>A
NM_000086.2:c.175G>A
NM_001042432.2:c.175G>AMANE SELECT
NM_001286104.2:c.175G>A
NM_001286105.2:c.-46G>A
NM_001286109.2:c.13G>A
NM_001286110.2:c.13G>A
NP_000077.1:p.Ala59Thr
NP_001035897.1:p.Ala59Thr
NP_001273033.1:p.Ala59Thr
NP_001273038.1:p.Ala5Thr
NP_001273039.1:p.Ala5Thr
LRG_689t1:c.175G>A
LRG_689t2:c.175G>A
LRG_689:g.7966G>A
LRG_689p1:p.Ala59Thr
NC_000016.9:g.28500658C>T
NM_001042432.1:c.175G>A
NM_001042432.2:c.175G>A

Protein change:

A59T

Links:

dbSNP: rs765893479

NCBI 1000 Genomes Browser:

rs765893479

Molecular consequence:

NM_001286105.2:c.-46G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000086.2:c.175G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001042432.2:c.175G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001286104.2:c.175G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001286109.2:c.13G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001286110.2:c.13G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Neuronal ceroid lipofuscinosis
Synonyms:: Ceroid storage disease
Identifiers:: MONDO: MONDO:0016295; MedGen: C0027877; Orphanet: 79263; OMIM: PS256730

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Homo sapiens solute carrier family 22 (organic cation transporter), member 2, mRNA (cDNA clone MGC:47742 IMAGE:5186229), complete cds
gi|25058304|gb|BC039899.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001394774	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 3, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 30446867, 28492532
SCV002074336	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Jan 19, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 33507216, 30446867, 27104957, 33497524, 29753273 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001394774

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 3, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV002074336

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Jan 19, 2022)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Retinal Phenotype of Patients With Isolated Retinal Degeneration Due to CLN3 Pathogenic Variants in a French Retinitis Pigmentosa Cohort.

Smirnov VM, Nassisi M, Solis Hernandez C, Méjécase C, El Shamieh S, Condroyer C, Antonio A, Meunier I, Andrieu C, Defoort-Dhellemmes S, Mohand-Said S, Sahel JA, Audo I, Zeitz C.

JAMA Ophthalmol. 2021 Mar 1;139(3):278-291. doi: 10.1001/jamaophthalmol.2020.6089. Erratum in: JAMA Ophthalmol. 2021 Dec 1;139(12):1324. doi: 10.1001/jamaophthalmol.2021.4737.

PubMed [citation]

PMID:: 33507216
PMCID:: PMC7844693

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001394774.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 59 of the CLN3 protein (p.Ala59Thr). This variant is present in population databases (rs765893479, gnomAD 0.004%). This missense change has been observed in individual(s) with retinitis pigmentosa (PMID: 30446867; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 950856). 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. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002074336.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Variant summary: CLN3 c.175G>A (p.Ala59Thr) 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 allele was found at a frequency of 2e-05 in 249916 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.175G>A has been reported in the literature in an individual with late-onset non-syndromic CLN3-associated retinitis pigmentosa (Zhang_2018, Chen_2019). Additionally, one clinical diagnostic lab has reported the variant to be observed in individual(s) with retinitis pigmentosa which has been observed to segregate with diease in related individuals (Invitae via ClinVar). In functional studies, the variant was reported to lead to altered splicing (Chen_2019). Correction of the c.175G>A variant restored CLN3 mRNA and protein expression, prevented accumulation of SCMAS, and reduced vacuolization of photoreceptor inner segments (Zhang_2020). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 26, 2024

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