NM_018941.4(CLN8):c.611G>T (p.Arg204Leu) AND Neuronal ceroid lipofuscinosis

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Oct 14, 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:: RCV000632701.4

Allele description [Variation Report for NM_018941.4(CLN8):c.611G>T (p.Arg204Leu)]

NM_018941.4(CLN8):c.611G>T (p.Arg204Leu)

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.611G>T (p.Arg204Leu)

HGVS:

NC_000008.11:g.1780317G>T
NG_008656.2:g.29540G>T
NM_018941.4:c.611G>TMANE SELECT
NP_061764.2:p.Arg204Leu
NP_061764.2:p.Arg204Leu
LRG_691t1:c.611G>T
LRG_691:g.29540G>T
LRG_691p1:p.Arg204Leu
NC_000008.10:g.1728483G>T
NM_018941.3:c.611G>T
Q9UBY8:p.Arg204Leu

Protein change:

R204L

Links:

UniProtKB: Q9UBY8#VAR_075367; dbSNP: rs386834134

NCBI 1000 Genomes Browser:

rs386834134

Molecular consequence:

NM_018941.4:c.611G>T - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000753887	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Oct 14, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 15024724, 25326637, 19807737, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000753887

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Oct 14, 2022)

germline

clinical testing

PubMed (4)
[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

Clinical exome sequencing for genetic identification of rare Mendelian disorders.

Lee H, Deignan JL, Dorrani N, Strom SP, Kantarci S, Quintero-Rivera F, Das K, Toy T, Harry B, Yourshaw M, Fox M, Fogel BL, Martinez-Agosto JA, Wong DA, Chang VY, Shieh PB, Palmer CG, Dipple KM, Grody WW, Vilain E, Nelson SF.

JAMA. 2014 Nov 12;312(18):1880-7. doi: 10.1001/jama.2014.14604.

PubMed [citation]

PMID:: 25326637
PMCID:: PMC4278636

See all PubMed Citations (4)

Details of each submission

From Invitae, SCV000753887.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg204 amino acid residue in CLN8. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15024724, 25326637; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 CLN8 protein function. ClinVar contains an entry for this variant (Variation ID: 56715). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 19807737). This variant is present in population databases (rs386834134, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 204 of the CLN8 protein (p.Arg204Leu).

#	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: Feb 28, 2024

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