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NM_017882.3(CLN6):c.150C>G (p.Tyr50Ter) AND Neuronal ceroid lipofuscinosis

Germline classification:
Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:
Sep 28, 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:
RCV000702360.8

Allele description [Variation Report for NM_017882.3(CLN6):c.150C>G (p.Tyr50Ter)]

NM_017882.3(CLN6):c.150C>G (p.Tyr50Ter)

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.150C>G (p.Tyr50Ter)
Other names:
Tyyr50X
HGVS:
  • NC_000015.10:g.68218584G>C
  • NG_008764.2:g.43628C>G
  • NM_017882.3:c.150C>GMANE SELECT
  • NP_060352.1:p.Tyr50Ter
  • LRG_832t1:c.150C>G
  • LRG_832:g.43628C>G
  • LRG_832p1:p.Tyr50Ter
  • NC_000015.9:g.68510922G>C
  • NG_008764.1:g.16159C>G
  • NM_017882.2:c.150C>G
Protein change:
Y50*
Links:
dbSNP: rs154774640
NCBI 1000 Genomes Browser:
rs154774640
Molecular consequence:
  • NM_017882.3:c.150C>G - nonsense - [Sequence Ontology: SO:0001587]

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
SCV000831212Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Sep 28, 2023)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV003844709Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)
Likely pathogenic
(Feb 2, 2023)
germlineclinical testing

PubMed (9)
[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

Variant late infantile ceroid lipofuscinoses associated with novel mutations in CLN6.

Cannelli N, Garavaglia B, Simonati A, Aiello C, Barzaghi C, Pezzini F, Cilio MR, Biancheri R, Morbin M, Dalla Bernardina B, Granata T, Tessa A, Invernizzi F, Pessagno A, Boldrini R, Zibordi F, Grazian L, Claps D, Carrozzo R, Mole SE, Nardocci N, Santorelli FM.

Biochem Biophys Res Commun. 2009 Feb 20;379(4):892-7. doi: 10.1016/j.bbrc.2008.12.159. Epub 2009 Jan 7.

PubMed [citation]
PMID:
19135028

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 (11)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000831212.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change creates a premature translational stop signal (p.Tyr50*) in the CLN6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CLN6 are known to be pathogenic (PMID: 19135028). This variant is present in population databases (rs154774640, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 21549341, 26075876). ClinVar contains an entry for this variant (Variation ID: 68094). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003844709.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (9)

Description

Variant summary: CLN6 c.150C>G (p.Tyr50X) 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 associated with Neuronal Ceroid Lipofuscinosis (NCL) in HGMD. The variant allele was found at a frequency of 8e-06 in 251404 control chromosomes. c.150C>G has been reported in the literature in individuals affected with Neuronal Ceroid-Lipofuscinosis (DiFruscio_2015), and specifically in Kufs disease, a subtype of NCL (Arsov_2011, Talbot_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Laboratories classified the variant as pathogenic (n=1) or likely pathogenic (n=2). 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: Oct 20, 2024