NM_001287.6(CLCN7):c.2144A>G (p.Tyr715Cys) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: May 23, 2022
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:: RCV000412760.8

Allele description [Variation Report for NM_001287.6(CLCN7):c.2144A>G (p.Tyr715Cys)]

NM_001287.6(CLCN7):c.2144A>G (p.Tyr715Cys)

Gene:

CLCN7:chloride voltage-gated channel 7 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16p13.3

Genomic location:

Preferred name:

NM_001287.6(CLCN7):c.2144A>G (p.Tyr715Cys)

HGVS:

NC_000016.10:g.1447498T>C
NG_007567.1:g.32587A>G
NM_001114331.3:c.2072A>G
NM_001287.6:c.2144A>GMANE SELECT
NP_001107803.1:p.Tyr691Cys
NP_001278.1:p.Tyr715Cys
NC_000016.9:g.1497499T>C
NM_001287.5:c.2144A>G

Protein change:

Y691C; TYR715CYS

Links:

OMIM: 602727.0007; dbSNP: rs1057517718

NCBI 1000 Genomes Browser:

rs1057517718

Molecular consequence:

NM_001114331.3:c.2072A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001287.6:c.2144A>G - 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
SCV000490474	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Pathogenic (Mar 19, 2018)	germline	clinical testing	Citation Link,
SCV002231960	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 23, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31155284, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000490474

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Pathogenic
(Mar 19, 2018)

germline

clinical testing

Citation Link,

SCV002231960

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(May 23, 2022)

germline

clinical testing

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

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

Citations

PubMed

Lysosomal Storage and Albinism Due to Effects of a De Novo CLCN7 Variant on Lysosomal Acidification.

Nicoli ER, Weston MR, Hackbarth M, Becerril A, Larson A, Zein WM, Baker PR 2nd, Burke JD, Dorward H, Davids M, Huang Y, Adams DR, Zerfas PM, Chen D, Markello TC, Toro C, Wood T, Elliott G, Vu M; Undiagnosed Diseases Network., Zheng W, Garrett LJ, et al.

Am J Hum Genet. 2019 Jun 6;104(6):1127-1138. doi: 10.1016/j.ajhg.2019.04.008. Epub 2019 May 30.

PubMed [citation]

PMID:: 31155284
PMCID:: PMC6562152

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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From GeneDx, SCV000490474.2

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

Description

The Y715C pathogenic variant in the CLCN7 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The Y715C variant was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Y715C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret Y715C as a pathogenic 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 Labcorp Genetics (formerly Invitae), Labcorp, SCV002231960.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CLCN7 function (PMID: 31155284). 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) performed at Invitae indicates that this missense variant is expected to disrupt CLCN7 protein function. ClinVar contains an entry for this variant (Variation ID: 372326). This missense change has been observed in individual(s) with hypopigmentation, organomegaly, and delayed myelination and development (PMID: 31155284). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 715 of the CLCN7 protein (p.Tyr715Cys).

#	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: Sep 29, 2024

ClinVar

Relating variation to medicine