NM_017882.3(CLN6):c.407G>A (p.Arg136His) AND Neuronal ceroid lipofuscinosis

Clinical significance:Likely pathogenic (Last evaluated: Sep 15, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001379796.1

Allele description [Variation Report for NM_017882.3(CLN6):c.407G>A (p.Arg136His)]

NM_017882.3(CLN6):c.407G>A (p.Arg136His)

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.407G>A (p.Arg136His)
HGVS:
  • NC_000015.10:g.68211754C>T
  • NG_008764.2:g.50458G>A
  • NM_017882.3:c.407G>AMANE SELECT
  • NP_060352.1:p.Arg136His
  • LRG_832t1:c.407G>A
  • LRG_832:g.50458G>A
  • LRG_832p1:p.Arg136His
  • NC_000015.9:g.68504092C>T
  • NM_017882.2:c.407G>A
Protein change:
R136H
Links:
dbSNP: rs769701646
NCBI 1000 Genomes Browser:
rs769701646
Molecular consequence:
  • NM_017882.3:c.407G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Neuronal ceroid lipofuscinosis
Synonyms:
Ceroid storage disease; Lipofuscin 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
SCV001577667Invitaecriteria provided, single submitter
Likely pathogenic
(Sep 15, 2020)
germlineclinical testing

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

Summary from all submissions

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

Citations

PubMed

[Clinical, genetic and pathological features of neuronal ceroid lipofuscinosis in 5 Chinese patients].

Ren SC, Gao BQ, Wang YJ, Wu XJ, Tian ZX, Sun YL.

Zhonghua Yi Xue Za Zhi. 2016 Nov 22;96(43):3504-3507. doi: 10.3760/cma.j.issn.0376-2491.2016.43.013. Chinese.

PubMed [citation]
PMID:
27903347

Lysoplex: An efficient toolkit to detect DNA sequence variations in the autophagy-lysosomal pathway.

Di Fruscio G, Schulz A, De Cegli R, Savarese M, Mutarelli M, Parenti G, Banfi S, Braulke T, Nigro V, Ballabio A.

Autophagy. 2015;11(6):928-38. doi: 10.1080/15548627.2015.1043077.

PubMed [citation]
PMID:
26075876
PMCID:
PMC4502703
See all PubMed Citations (5)

Details of each submission

From Invitae, SCV001577667.1

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

Description

This sequence change replaces arginine with histidine at codon 136 of the CLN6 protein (p.Arg136His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant has been observed in individual(s) with clinical features of neuronal ceroid lipofuscinosis (PMID: 27903347, 26075876, 30561534). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 402184). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Arg136 amino acid residue in CLN6. Other variant(s) that disrupt this residue have been observed in individuals with CLN6-related conditions (PMID: 19135028), which suggests that this may be a clinically significant amino acid residue. 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.

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

Last Updated: Oct 7, 2021

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