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NM_017882.3(CLN6):c.679G>A (p.Glu227Lys) AND Ceroid lipofuscinosis, neuronal, 6A

Germline classification:
Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:
Apr 13, 2023
Review status:
criteria provided, conflicting classifications
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:
RCV000625854.16

Allele description [Variation Report for NM_017882.3(CLN6):c.679G>A (p.Glu227Lys)]

NM_017882.3(CLN6):c.679G>A (p.Glu227Lys)

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.679G>A (p.Glu227Lys)
HGVS:
  • NC_000015.10:g.68208397C>T
  • NG_008764.2:g.53815G>A
  • NM_017882.3:c.679G>AMANE SELECT
  • NP_060352.1:p.Glu227Lys
  • LRG_832t1:c.679G>A
  • LRG_832:g.53815G>A
  • LRG_832p1:p.Glu227Lys
  • NC_000015.9:g.68500735C>T
  • NM_017882.2:c.679G>A
  • p.Glu227Lys
Protein change:
E227K
Links:
dbSNP: rs746753722
NCBI 1000 Genomes Browser:
rs746753722
Molecular consequence:
  • NM_017882.3:c.679G>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Name:
Ceroid lipofuscinosis, neuronal, 6A
Synonyms:
Neuronal ceroid lipofuscinosis, Gypsy/Indian early juvenile variant; Neuronal ceroid lipofuscinosis 6; CLN6-Related Neuronal Ceroid-Lipofuscinosis
Identifiers:
MONDO: MONDO:0011144; MedGen: C5551375; Orphanet: 168491; OMIM: 601780

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000746423Genomic Research Center, Shahid Beheshti University of Medical Sciences
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Dec 3, 2017) 		inheritedclinical testing

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

SCV001132554Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain significance
(Nov 15, 2018) 		germlineresearch

PubMed (2)
[See all records that cite these PMIDs]

SCV003915841Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely pathogenic
(Apr 13, 2023) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes1not providednot providednot providednot providedresearch, clinical testing
not providedinheritedyesnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Hereditary spastic paraplegia in Greece: characterisation of a previously unexplored population using next-generation sequencing.

Lynch DS, Koutsis G, Tucci A, Panas M, Baklou M, Breza M, Karadima G, Houlden H.

Eur J Hum Genet. 2016 Jun;24(6):857-63. doi: 10.1038/ejhg.2015.200. Epub 2015 Sep 16.

PubMed [citation]
PMID:
26374131
PMCID:
PMC4688955

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Genomic Research Center, Shahid Beheshti University of Medical Sciences, SCV000746423.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1inheritedyesnot providednot providednot providednot providednot providednot providednot provided

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001132554.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedresearch PubMed (2)

Description

The homozygous p.Glu227Lys variant in CLN6 was identified by our study in one individual with Neuronal Ceroid Lipofuscinosis. This variant has been identified in the literature in the case of one affected homozygous 19-year old male (Lynch et al. 2016, PMID: 26374131). This variant has been identified in <0.01% (1/15038) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs746753722). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Pro441Leu variant is uncertain.

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

From Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics, SCV003915841.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
11not providednot providedclinical testing PubMed (1)

Description

A Homozygous missense variation in exon 7 of the CLN6 gene that results in the amino acid substitution of Lysine for Glutamic acid at codon 227 was detected. The observed variant c.679G>A (p.Glu227Lys) has not been reported in the 1000 genomes and has a MAF of 0.0012% in the gnomAD databases. The in silico prediction of the variant are possibly damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as likely pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided1not providednot providednot provided

Last Updated: Oct 26, 2024