NM_006493.4(CLN5):c.777_778del (p.Phe260fs) AND Neuronal ceroid lipofuscinosis

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Nov 1, 2023
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:: RCV000468638.11

Allele description [Variation Report for NM_006493.4(CLN5):c.777_778del (p.Phe260fs)]

NM_006493.4(CLN5):c.777_778del (p.Phe260fs)

Gene:

CLN5:CLN5 intracellular trafficking protein [Gene - OMIM - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

13q22.3

Genomic location:

Preferred name:

NM_006493.4(CLN5):c.777_778del (p.Phe260fs)

HGVS:

NC_000013.11:g.77000667AT[1]
NG_009064.1:g.13744AT[1]
NM_001366624.2:c.*224AT[1]
NM_006493.4:c.777_778delMANE SELECT
NP_006484.2:p.Phe260fs
LRG_692t1:c.924_925del
LRG_692:g.13744AT[1]
NC_000013.10:g.77574802AT[1]
NC_000013.10:g.77574802_77574803del
NM_006493.2:c.924_925del
NM_006493.2:c.924_925delAT

Protein change:

F260fs

Links:

dbSNP: rs786204644

NCBI 1000 Genomes Browser:

rs786204644

Molecular consequence:

NM_001366624.2:c.*224AT[1] - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_006493.4:c.777_778del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

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

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Rattus norvegicus ADCYAP receptor type I (Adcyap1r1), transcript variant 2, mRNA
Rattus norvegicus ADCYAP receptor type I (Adcyap1r1), transcript variant 2, mRNA
gi|396080324|ref|NM_133511.2|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000549225	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 1, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 22532218, 9662406, 28492532
SCV000919231	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (May 19, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000549225

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 1, 2023)

germline

clinical testing

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

SCV000919231

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(May 19, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link

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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

CLN5, a novel gene encoding a putative transmembrane protein mutated in Finnish variant late infantile neuronal ceroid lipofuscinosis.

Savukoski M, Klockars T, Holmberg V, Santavuori P, Lander ES, Peltonen L.

Nat Genet. 1998 Jul;19(3):286-8.

PubMed [citation]

PMID:: 9662406

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 (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000549225.8

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

Description

This sequence change creates a premature translational stop signal (p.Phe309Serfs*12) in the CLN5 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 99 amino acid(s) of the CLN5 protein. This variant is present in population databases (rs769059034, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 22532218). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 189038). This variant disrupts a region of the CLN5 protein in which other variant(s) (p.Tyr392*) have been determined to be pathogenic (PMID: 9662406). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

#	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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000919231.2

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

Description

Variant summary: CLN5 c.924_925delAT (p.Phe309SerfsX12) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 3.6e-05 in 251266 control chromosomes, predominantly at a frequency of 0.00026 within the Latino subpopulation in the gnomAD database. c.924_925delAT has been reported in the literature in one individual affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Two laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

#	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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