NM_018941.4(CLN8):c.709G>A (p.Gly237Arg) AND Neuronal ceroid lipofuscinosis

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jun 20, 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:: RCV003532006.2

Allele description [Variation Report for NM_018941.4(CLN8):c.709G>A (p.Gly237Arg)]

NM_018941.4(CLN8):c.709G>A (p.Gly237Arg)

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.709G>A (p.Gly237Arg)

Other names:

p.G237R:GGA>AGA

HGVS:

NC_000008.11:g.1780415G>A
NG_008656.2:g.29638G>A
NM_018941.4:c.709G>AMANE SELECT
NP_061764.2:p.Gly237Arg
NP_061764.2:p.Gly237Arg
LRG_691t1:c.709G>A
LRG_691:g.29638G>A
LRG_691p1:p.Gly237Arg
NC_000008.10:g.1728581G>A
NM_018941.3:c.709G>A
Q9UBY8:p.Gly237Arg

Protein change:

G237R

Links:

UniProtKB: Q9UBY8#VAR_058439; dbSNP: rs746645358

NCBI 1000 Genomes Browser:

rs746645358

Molecular consequence:

NM_018941.4:c.709G>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004294541	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jun 20, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 19201763, 19807737, 21990111, 33358637, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004294541

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jun 20, 2023)

germline

clinical testing

PubMed (5)
[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

Mutations in CLN7/MFSD8 are a common cause of variant late-infantile neuronal ceroid lipofuscinosis.

Kousi M, Siintola E, Dvorakova L, Vlaskova H, Turnbull J, Topcu M, Yuksel D, Gokben S, Minassian BA, Elleder M, Mole SE, Lehesjoki AE.

Brain. 2009 Mar;132(Pt 3):810-9. doi: 10.1093/brain/awn366. Epub 2009 Feb 5.

PubMed [citation]

PMID:: 19201763

Novel CLN8 mutations confirm the clinical and ethnic diversity of late infantile neuronal ceroid lipofuscinosis.

Reinhardt K, Grapp M, Schlachter K, Brück W, Gärtner J, Steinfeld R.

Clin Genet. 2010 Jan;77(1):79-85. doi: 10.1111/j.1399-0004.2009.01285.x. Epub 2009 Oct 5.

PubMed [citation]

PMID:: 19807737

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004294541.1

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

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. 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: 188917). This missense change has been observed in individuals with neuronal ceroid lipofuscinosis (PMID: 19201763, 19807737, 21990111, 33358637). This variant is present in population databases (rs746645358, gnomAD 0.007%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 237 of the CLN8 protein (p.Gly237Arg).

#	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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