VCV000136802.53 - ClinVar

NM_017882.3(CLN6):c.34G>A (p.Ala12Thr)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(15)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Uncertain significance(1); Benign(8); Likely benign(3)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_017882.3(CLN6):c.34G>A (p.Ala12Thr)

Variation ID: 136802 Accession: VCV000136802.53

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 15q23 15: 68229551 (GRCh38) [ NCBI UCSC ] 15: 68521889 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Oct 5, 2015	Oct 20, 2024	Aug 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_017882.3:c.34G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_060352.1:p.Ala12Thr	missense
NC_000015.10:g.68229551C>T
NC_000015.9:g.68521889C>T
NG_008764.2:g.32661G>A
LRG_832:g.32661G>A
LRG_832t1:c.34G>A	LRG_832p1:p.Ala12Thr
	Q9NWW5:p.Ala12Thr

... more HGVS ... less HGVS

Protein change

A12T

Other names

p.A12T:GCG>ACG
NM_017882.2(CLN6):c.34G>A(p.Ala12Thr)

Canonical SPDI

NC_000015.10:68229550:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00339 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 0.00339

1000 Genomes Project 30x 0.00406

Exome Aggregation Consortium (ExAC) 0.00502

The Genome Aggregation Database (gnomAD), exomes 0.01000

Trans-Omics for Precision Medicine (TOPMed) 0.01031

The Genome Aggregation Database (gnomAD) 0.01081

Links

ClinGen: CA302669 UniProtKB: Q9NWW5#VAR_066904 dbSNP: rs112239768 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
CLN6		-	-	GRCh38 GRCh37	767	783

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not specified	Benign/Likely benign (3)	criteria provided, multiple submitters, no conflicts	Dec 10, 2021	RCV000173024.20
Ceroid lipofuscinosis, neuronal, 6A	Benign (1)	criteria provided, single submitter	May 31, 2018	RCV000677327.9
not provided	Benign (6)	criteria provided, multiple submitters, no conflicts	Aug 1, 2024	RCV000675965.36
Neuronal ceroid lipofuscinosis	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Feb 1, 2024	RCV000989355.23
Inborn genetic diseases	Benign (1)	criteria provided, single submitter	May 24, 2017	RCV002312552.9
Ceroid lipofuscinosis, neuronal, 6A Ceroid lipofuscinosis, neuronal, 6B (Kufs type)	Likely benign (1)	criteria provided, single submitter	Nov 1, 2021	RCV003224161.8

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Benign (May 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Ceroid lipofuscinosis, neuronal, 6A Affected status: unknown Allele origin: unknown	SIB Swiss Institute of Bioinformatics Accession: SCV000803558.1 First in ClinVar: Aug 20, 2018 Last updated: Aug 20, 2018	Comment: This variant is interpreted as a Benign, for Ceroid lipofuscinosis, neuronal, 6, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BS1 => Allele … (more) This variant is interpreted as a Benign, for Ceroid lipofuscinosis, neuronal, 6, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BS1 => Allele frequency is greater than expected for disorder. BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. (less)
Benign (Jan 29, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000202487.7 First in ClinVar: Feb 02, 2015 Last updated: May 03, 2018	Publications: PubMed (1) PubMed: 21990111 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CLN6 Number of individuals with the variant: 11 Sex: mixed
Benign (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Neuronal ceroid lipofuscinosis 1 Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001139646.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
Likely benign (Dec 10, 2021)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002050988.1 First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022
Benign (Dec 12, 2018)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000167774.14 First in ClinVar: Jun 23, 2014 Last updated: Mar 04, 2023	Comment: This variant is associated with the following publications: (PMID: 21990111, 29482223)
Likely benign (Nov 01, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Ceroid lipofuscinosis, neuronal, 6B (Kufs type) Ceroid lipofuscinosis, neuronal, 6A Affected status: unknown Allele origin: germline	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago Accession: SCV003919810.1 First in ClinVar: Apr 30, 2023 Last updated: Apr 30, 2023	Comment: CLN6 NM_017882.2 p.Ala12Thr (c.34G>A): This variant has been reported in the literature in at least 2 individuals (1 with neuronal ceroid lipofuscinosis and 1 with … (more) CLN6 NM_017882.2 p.Ala12Thr (c.34G>A): This variant has been reported in the literature in at least 2 individuals (1 with neuronal ceroid lipofuscinosis and 1 with cerebellar ataxia) (Kousi 2012 PMID:21990111, Coutelier 2018 PMID:29482223). However, this variant is present in 1.7% (1216/67944) of European alleles including 11 homozygotes in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/15-68229551-C-T?dataset=gnomad_r3). Evolutionary conservation and computational predictive tools for this variant are unclear. This variant is present in ClinVar, with several labs classifying this variant as Likely Benign or Benign (Variation ID:136802). In summary, data on this variant suggests that this variant does not cause disease, but requires further evidence. Therefore this variant is classified as likely benign. (less)
Benign (Feb 01, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Neuronal ceroid lipofuscinosis Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000290387.10 First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024
Benign (Nov 22, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000603089.4 First in ClinVar: Oct 05, 2015 Last updated: Feb 20, 2024
Likely benign (Apr 16, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000247043.1 First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015
Uncertain significance (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Neuronal ceroid lipofuscinosis Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001278035.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Benign (May 24, 2017)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000846696.4 First in ClinVar: Nov 08, 2018 Last updated: May 01, 2024	Comment: This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more) This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Benign (Aug 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV002822193.14 First in ClinVar: Jan 21, 2023 Last updated: Oct 20, 2024	Comment: CLN6: PP3, BS1, BS2 Number of individuals with the variant: 35
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001739970.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001928319.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Uncertain significance (Apr 19, 2017)	no assertion criteria provided Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV000801694.1 First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018
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Comment:

This variant is interpreted as a Benign, for Ceroid lipofuscinosis, neuronal, 6, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BS1 => Allele frequency is greater than expected for disorder. BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.

Comment:

CLN6 NM_017882.2 p.Ala12Thr (c.34G>A): This variant has been reported in the literature in at least 2 individuals (1 with neuronal ceroid lipofuscinosis and 1 with cerebellar ataxia) (Kousi 2012 PMID:21990111, Coutelier 2018 PMID:29482223). However, this variant is present in 1.7% (1216/67944) of European alleles including 11 homozygotes in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/15-68229551-C-T?dataset=gnomad_r3). Evolutionary conservation and computational predictive tools for this variant are unclear. This variant is present in ClinVar, with several labs classifying this variant as Likely Benign or Benign (Variation ID:136802). In summary, data on this variant suggests that this variant does not cause disease, but requires further evidence. Therefore this variant is classified as likely benign.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Comment:

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Update of the mutation spectrum and clinical correlations of over 360 mutations in eight genes that underlie the neuronal ceroid lipofuscinoses.	Kousi M	Human mutation	2012	PMID: 21990111
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CLN6	-	-	-	-

Text-mined citations for rs112239768 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_017882.3(CLN6):c.34G>A (p.Ala12Thr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs112239768 ...