NM_006493.4(CLN5):c.398T>G (p.Met133Arg) AND Neuronal ceroid lipofuscinosis 5

Germline classification:: Uncertain significance (4 submissions)
Last evaluated:: Mar 21, 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:: RCV000784980.9

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]

Observations:

Condition(s)

Name:: Neuronal ceroid lipofuscinosis 5 (CLN5)
Synonyms:: CEROID LIPOFUSCINOSIS, NEURONAL, 5, VARIABLE AGE AT ONSET; Neuronal ceroid lipofuscinosis Finnish variant; NEURONAL CEROID LIPOFUSCINOSIS, LATE INFANTILE, FINNISH VARIANT; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009745; MedGen: C1850442; Orphanet: 168491; Orphanet: 228360; OMIM: 256731

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000923527	Genomic Research Center, Shahid Beheshti University of Medical Sciences	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 1, 2019)	inherited	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002027061	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Sep 5, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003852664	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 21, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004048090	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	inherited	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Genomic Research Center, Shahid Beheshti University of Medical Sciences, SCV000923527.1

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

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

From Genome-Nilou Lab, SCV002027061.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics, SCV003852664.1

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

Description

A heterozygous missense variant in exon 3 of the CLN5 gene that results in the amino acid substitution of Arginine for Methionine at codon 133 (p.Met133Arg) was detected. The p.Met133Arg variant has not been reported in the 1000 genomes, gnomAD (v3.1), gnomdAD (v2) and topmed databases. The in silico predictions of the variant are possibly damaging by PolyPhen-2 (HumDiv) and damaging by SIFT and LRT. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as variant of uncertain significance.

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

From Neuberg Centre For Genomic Medicine, NCGM, SCV004048090.1

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

Description

The missense variant c.398T>G (p.Met133Arg) in CLN5 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Met133Arg variant is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Uncertain Significance. The amino acid Met at position 133 is changed to a Arg changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Met133Arg in CLN5 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance

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

Last Updated: Sep 29, 2024

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