NM_006493.4(CLN5):c.812A>G (p.Asn271Ser) AND Neuronal ceroid lipofuscinosis

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Oct 18, 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:: RCV000230950.8

Allele description [Variation Report for NM_006493.4(CLN5):c.812A>G (p.Asn271Ser)]

NM_006493.4(CLN5):c.812A>G (p.Asn271Ser)

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.812A>G (p.Asn271Ser)

HGVS:

NC_000013.11:g.77000704A>G
NG_009064.1:g.13781A>G
NM_001366624.2:c.*261A>G
NM_006493.4:c.812A>GMANE SELECT
NP_006484.2:p.Asn271Ser
LRG_692t1:c.959A>G
LRG_692:g.13781A>G
NC_000013.10:g.77574839A>G
NM_006493.2:c.959A>G

Protein change:

N271S

Links:

dbSNP: rs199609750

NCBI 1000 Genomes Browser:

rs199609750

Molecular consequence:

NM_001366624.2:c.*261A>G - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_006493.4:c.812A>G - 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
SCV000289545	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 18, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 30037983, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000289545

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 18, 2022)

germline

clinical testing

PubMed (2)
[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

An Alzheimer's Disease-Linked Loss-of-Function CLN5 Variant Impairs Cathepsin D Maturation, Consistent with a Retromer Trafficking Defect.

Qureshi YH, Patel VM, Berman DE, Kothiya MJ, Neufeld JL, Vardarajan B, Tang M, Reyes-Dumeyer D, Lantigua R, Medrano M, Jiménez-Velázquez IJ, Small SA, Reitz C.

Mol Cell Biol. 2018 Sep 28;38(20). doi:pii: e00011-18. 10.1128/MCB.00011-18. Print 2018 Oct 15.

PubMed [citation]

PMID:: 30037983
PMCID:: PMC6168984

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

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000289545.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 320 of the CLN5 protein (p.Asn320Ser). This variant is present in population databases (rs199609750, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with CLN5-related conditions. ClinVar contains an entry for this variant (Variation ID: 240660). 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 not expected to disrupt CLN5 protein function. Experimental studies have shown that this missense change affects CLN5 function (PMID: 30037983). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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: Oct 8, 2024

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