NM_017882.3(CLN6):c.728C>T (p.Ala243Val) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Sep 15, 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:: RCV000187103.11

Allele description [Variation Report for NM_017882.3(CLN6):c.728C>T (p.Ala243Val)]

NM_017882.3(CLN6):c.728C>T (p.Ala243Val)

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.728C>T (p.Ala243Val)

Other names:

p.A243V:GCC>GTC

HGVS:

NC_000015.10:g.68208348G>A
NG_008764.2:g.53864C>T
NM_017882.3:c.728C>TMANE SELECT
NP_060352.1:p.Ala243Val
LRG_832t1:c.728C>T
LRG_832:g.53864C>T
LRG_832p1:p.Ala243Val
NC_000015.9:g.68500686G>A
NM_017882.2:c.728C>T

Protein change:

A243V

Links:

dbSNP: rs767164948

NCBI 1000 Genomes Browser:

rs767164948

Molecular consequence:

NM_017882.3:c.728C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000240678	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Uncertain significance (Jun 25, 2018)	germline	clinical testing	Citation Link,
SCV004564193	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Uncertain significance (Sep 15, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000240678

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Uncertain significance
(Jun 25, 2018)

germline

clinical testing

Citation Link,

SCV004564193

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process 2024)

Uncertain significance
(Sep 15, 2023)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Details of each submission

From GeneDx, SCV000240678.12

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

A variant of uncertain significance has been identified in the CLN6 gene. The A243V variant has been reported in two individuals with neuronal ceroid lipofuscinosis who were heterozygous for this change; however, a second CLN6 variant was not detected and information regarding parental testing was not provided (Di Fruscio et al., 2015). The A243V variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The A243V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV004564193.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The CLN6 c.728C>T; p.Ala243Val variant (rs767164948) is reported in the literature in two individuals affected with neuronal ceroid lipofuscinosis (Di Fruscio 2015). This variant is also reported in ClinVar (Variation ID: 205174) and is found in the non-Finnish European population with an allele frequency of 0.005% (6/128900 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is deleterious (REVEL: 0.765). However, given the lack of clinical and functional data, the significance of this variant is uncertain at this time. References: Di Fruscio G et al. Lysoplex: An efficient toolkit to detect DNA sequence variations in the autophagy-lysosomal pathway. Autophagy. 2015;11(6):928-38. PMID: 26075876.

#	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: Jun 29, 2024

ClinVar

Relating variation to medicine