NM_018941.4(CLN8):c.763C>T (p.Gln255Ter) AND Neuronal ceroid lipofuscinosis

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 9, 2022
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:: RCV002544675.3

Allele description [Variation Report for NM_018941.4(CLN8):c.763C>T (p.Gln255Ter)]

NM_018941.4(CLN8):c.763C>T (p.Gln255Ter)

Gene:

CLN8:CLN8 transmembrane ER and ERGIC protein [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

8p23.3

Genomic location:

Preferred name:

NM_018941.4(CLN8):c.763C>T (p.Gln255Ter)

HGVS:

NC_000008.11:g.1780469C>T
NG_008656.2:g.29692C>T
NM_018941.4:c.763C>TMANE SELECT
NP_061764.2:p.Gln255Ter
NP_061764.2:p.Gln255Ter
LRG_691t1:c.763C>T
LRG_691:g.29692C>T
LRG_691p1:p.Gln255Ter
NC_000008.10:g.1728635C>T
NM_018941.3:c.763C>T

Protein change:

Q255*

Links:

dbSNP: rs746397087

NCBI 1000 Genomes Browser:

rs746397087

Molecular consequence:

NM_018941.4:c.763C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003440633	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 9, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 15024724, 28116333, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003440633

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 9, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

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

Variant late infantile neuronal ceroid lipofuscinosis in a subset of Turkish patients is allelic to Northern epilepsy.

Ranta S, Topcu M, Tegelberg S, Tan H, Ustübütün A, Saatci I, Dufke A, Enders H, Pohl K, Alembik Y, Mitchell WA, Mole SE, Lehesjoki AE.

Hum Mutat. 2004 Apr;23(4):300-5.

PubMed [citation]

PMID:: 15024724

CLN8 disease caused by large genomic deletions.

Beesley C, Guerreiro RJ, Bras JT, Williams RE, Taratuto AL, Eltze C, Mole SE.

Mol Genet Genomic Med. 2017 Jan;5(1):85-91. doi: 10.1002/mgg3.263.

PubMed [citation]

PMID:: 28116333
PMCID:: PMC5241206

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003440633.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the CLN8 protein in which other variant(s) (p.Trp263Cys) have been determined to be pathogenic (PMID: 15024724; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 558594). This premature translational stop signal has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 28116333). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs746397087, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Gln255*) in the CLN8 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 32 amino acid(s) of the CLN8 protein.

#	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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