NM_017882.3(CLN6):c.722T>C (p.Met241Thr) AND Neuronal ceroid lipofuscinosis

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jun 5, 2019
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:: RCV001203261.7

Allele description [Variation Report for NM_017882.3(CLN6):c.722T>C (p.Met241Thr)]

NM_017882.3(CLN6):c.722T>C (p.Met241Thr)

Gene:

CLN6:CLN6 transmembrane ER protein [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

15q23

Genomic location:

Preferred name:

NM_017882.3(CLN6):c.722T>C (p.Met241Thr)

HGVS:

NC_000015.10:g.68208354A>G
NG_008764.2:g.53858T>C
NM_017882.3:c.722T>CMANE SELECT
NP_060352.1:p.Met241Thr
LRG_832t1:c.722T>C
LRG_832:g.53858T>C
LRG_832p1:p.Met241Thr
NC_000015.9:g.68500692A>G
NM_017882.2:c.722T>C

Protein change:

M241T

Links:

dbSNP: rs1555438255

NCBI 1000 Genomes Browser:

rs1555438255

Molecular consequence:

NM_017882.3:c.722T>C - 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
SCV001374417	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jun 5, 2019)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 30561534, 18811591, 20430023, 12815591, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001374417

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jun 5, 2019)

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

Kufs disease due to mutation of CLN6: clinical, pathological and molecular genetic features.

Berkovic SF, Oliver KL, Canafoglia L, Krieger P, Damiano JA, Hildebrand MS, Morbin M, Vears DF, Sofia V, Giuliano L, Garavaglia B, Simonati A, Santorelli FM, Gambardella A, Labate A, Belcastro V, Castellotti B, Ozkara C, Zeman A, Rankin J, Mole SE, Aguglia U, et al.

Brain. 2019 Jan 1;142(1):59-69. doi: 10.1093/brain/awy297.

PubMed [citation]

PMID:: 30561534

Cln6 mutants associated with neuronal ceroid lipofuscinosis are degraded in a proteasome-dependent manner.

Oresic K, Mueller B, Tortorella D.

Biosci Rep. 2009 Jun;29(3):173-81. doi: 10.1042/BSR20080143.

PubMed [citation]

PMID:: 18811591
PMCID:: PMC2674128

See all PubMed Citations (5)

Details of each submission

From Invitae, SCV001374417.5

#	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. This variant disrupts the p.Met241 amino acid residue in CLN6. Other variant(s) that disrupt this residue have been observed in individuals with CLN6-related conditions (PMID: 30561534), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this variant disrupts the stability of the protein leading to rapid degradation (PMID: 18811591, 20430023). This variant has been observed in individuals affected with CLN6-related disease (PMID: 12815591, Invitae and External communication). ClinVar contains an entry for this variant (Variation ID: 431958). This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with threonine at codon 241 of the CLN6 protein (p.Met241Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine.

#	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 20, 2024

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