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

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Dec 20, 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:: RCV001379796.6

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
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
SCV001577667	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 20, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 26075876, 26539891, 27903347, 30561534, 34868216, 28492532
SCV003933968	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (May 8, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 26075876, 30561534, 26539891, 35505348, 34868216 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001577667

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 20, 2023)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV003933968

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(May 8, 2023)

germline

clinical testing

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

Citation Link

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

[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

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):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (7)

Details of each submission

From Invitae, SCV001577667.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 136 of the CLN6 protein (p.Arg136His). This variant is present in population databases (rs769701646, gnomAD 0.009%). This missense change has been observed in individual(s) with clinical features of neuronal ceroid lipofuscinosis (PMID: 26075876, 26539891, 27903347, 30561534, 34868216). 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: 402184). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CLN6 protein function. This variant disrupts the p.Arg136 amino acid residue in CLN6. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue 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, SCV003933968.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Variant summary: CLN6 c.407G>A (p.Arg136His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251264 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CLN6 causing Neuronal Ceroid-Lipofuscinosis (Batten Disease) (4e-05 vs 0.0011), allowing no conclusion about variant significance. c.407G>A has been reported in the literature as a biallelic genotype in multiple individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) and in one individual with clinical features within the spectrum of the disease phenotype (e.g. Karaca_2015, DiFruscio_2015, Berkovic_2019, Nicolaou_2021, Rus_2022). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30561534, 26075876, 26539891, 34868216, 35505348). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either VUS (n=2) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was 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

Last Updated: Feb 28, 2024

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