NM_006493.4(CLN5):c.398T>G (p.Met133Arg) AND Neuronal ceroid lipofuscinosis

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Nov 27, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000801114.9

Allele description [Variation Report for NM_006493.4(CLN5):c.398T>G (p.Met133Arg)]

NM_006493.4(CLN5):c.398T>G (p.Met133Arg)

Gene:

CLN5:CLN5 intracellular trafficking protein [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

13q22.3

Genomic location:

Preferred name:

NM_006493.4(CLN5):c.398T>G (p.Met133Arg)

Other names:

p.Met133Arg

HGVS:

NC_000013.11:g.76995960T>G
NG_009064.1:g.9037T>G
NM_001366624.2:c.398T>G
NM_006493.4:c.398T>GMANE SELECT
NP_001353553.1:p.Met133Arg
NP_006484.2:p.Met133Arg
LRG_692t1:c.545T>G
LRG_692:g.9037T>G
NC_000013.10:g.77570095T>G
NM_001366624.2:c.398T>G
NM_006493.2:c.545T>G

Protein change:

M133R

Links:

dbSNP: rs1419308949

NCBI 1000 Genomes Browser:

rs1419308949

Molecular consequence:

NM_001366624.2:c.398T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_006493.4:c.398T>G - 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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semaphorin 5A [Homo sapiens]
semaphorin 5A [Homo sapiens]
gi|4506881|ref|NP_003957.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000940873	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 27, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31741823, 28492532
SCV002087961	Natera, Inc.	no assertion criteria provided	Uncertain significance (Sep 2, 2021)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000940873

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 27, 2023)

germline

clinical testing

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

SCV002087961

Natera, Inc.

no assertion criteria provided

Uncertain significance
(Sep 2, 2021)

germline

clinical testing

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

High diagnostic yield of direct Sanger sequencing in the diagnosis of neuronal ceroid lipofuscinoses.

Jilani A, Matviychuk D, Blaser S, Dyack S, Mathieu J, Prasad AN, Prasad C, Kyriakopoulou L, Mercimek-Andrews S.

JIMD Rep. 2019 Nov;50(1):20-30. doi: 10.1002/jmd2.12057.

PubMed [citation]

PMID:: 31741823
PMCID:: PMC6850977

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

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000940873.4

#	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 methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 182 of the CLN5 protein (p.Met182Arg). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 31741823). ClinVar contains an entry for this variant (Variation ID: 634488). 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 CLN5 protein function with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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 Natera, Inc., SCV002087961.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	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: Sep 29, 2024

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