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NM_006493.4(CLN5):c.188G>A (p.Arg63His) AND Neuronal ceroid lipofuscinosis

Germline classification:
Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:
Jan 15, 2024
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:
RCV000698933.10

Allele description [Variation Report for NM_006493.4(CLN5):c.188G>A (p.Arg63His)]

NM_006493.4(CLN5):c.188G>A (p.Arg63His)

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.188G>A (p.Arg63His)
Other names:
R112H
HGVS:
  • NC_000013.11:g.76995077G>A
  • NG_009064.1:g.8154G>A
  • NM_001366624.2:c.188G>A
  • NM_006493.4:c.188G>AMANE SELECT
  • NP_001353553.1:p.Arg63His
  • NP_006484.2:p.Arg63His
  • LRG_692t1:c.335G>A
  • LRG_692:g.8154G>A
  • LRG_692p1:p.Arg112His
  • NC_000013.10:g.77569212G>A
  • NM_006493.2:c.335G>A
Protein change:
R63H; ARG112HIS
Links:
OMIM: 608102.0004; dbSNP: rs104894386
NCBI 1000 Genomes Browser:
rs104894386
Molecular consequence:
  • NM_001366624.2:c.188G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_006493.4:c.188G>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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000827624Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Jan 15, 2024)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV002087951Natera, Inc.
no assertion criteria provided
Likely pathogenic
(Apr 9, 2021)
germlineclinical testing

SCV004037644Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)
Likely pathogenic
(Aug 28, 2023)
germlineclinical testing

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

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Phenotype and natural history of variant late infantile ceroid-lipofuscinosis 5.

Simonati A, Williams RE, Nardocci N, Laine M, Battini R, Schulz A, Garavaglia B, Moro F, Pezzini F, Santorelli FM.

Dev Med Child Neurol. 2017 Aug;59(8):815-821. doi: 10.1111/dmcn.13473. Epub 2017 May 25.

PubMed [citation]
PMID:
28542837

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
See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000827624.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 112 of the CLN5 protein (p.Arg112His). This variant is present in population databases (rs104894386, gnomAD 0.003%). This missense change has been observed in individuals with juvenile onset neuronal ceroid lipofuscinosis (PMID: 15728307, 28542837, 30078242). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2567). 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 80%. Experimental studies have shown that this missense change affects CLN5 function (PMID: 20052765). This variant disrupts the p.Arg112 amino acid residue in CLN5. Other variant(s) that disrupt this residue have been observed in individuals with CLN5-related conditions (PMID: 30078242), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Natera, Inc., SCV002087951.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004037644.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

Variant summary: CLN5 c.188G>A (p.Arg63His), also referred to as p.Arg112His, results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251186 control chromosomes (gnomAD). c.188G>A has been reported in the literature in the homozygous state in two siblings and in at least one other unrelated individual affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) (e.g. Pineda-Trujilo_2005, Zhou_2018). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, indicating that the variant protein primarily localizes to the ER as opposed to the lysosome, however, it does not allow convincing conclusions about the variant effect (Schmiedt_2010). Other variants affecting the same amino acid (i.e. p.Arg63Cys, p.Arg63Pro) have been reported in association with Neuronal Ceroid-Lipofuscinosis in the HGMD database, suggesting Arg63 may be important for protein function, but this has yet to be determined conclusively. The following publications have been ascertained in the context of this evaluation (PMID: 15728307, 20052765, 30078242). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024