NM_000083.3(CLCN1):c.501C>G (p.Phe167Leu) AND not specified

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Jan 15, 2024
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:: RCV000479583.5

Allele description [Variation Report for NM_000083.3(CLCN1):c.501C>G (p.Phe167Leu)]

NM_000083.3(CLCN1):c.501C>G (p.Phe167Leu)

Gene:

CLCN1:chloride voltage-gated channel 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7q34

Genomic location:

Preferred name:

NM_000083.3(CLCN1):c.501C>G (p.Phe167Leu)

HGVS:

NC_000007.14:g.143321432C>G
NG_009815.2:g.10307C>G
NM_000083.3:c.501C>GMANE SELECT
NP_000074.3:p.Phe167Leu
NC_000007.13:g.143018525C>G
NG_009815.1:g.10307C>G
NM_000083.2:c.501C>G
NR_046453.2:n.603C>G
P35523:p.Phe167Leu

Protein change:

F167L

Links:

UniProtKB: P35523#VAR_001588; dbSNP: rs149729531

NCBI 1000 Genomes Browser:

rs149729531

Molecular consequence:

NM_000083.3:c.501C>G - missense variant - [Sequence Ontology: SO:0001583]
NR_046453.2:n.603C>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000564883	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Likely benign (Dec 28, 2017)	germline	clinical testing	Citation Link,
SCV004803337	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Jan 15, 2024)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 34106991, 33263785, 34529042, 36964972, 23933576, 28993909, 27266866, 10690989 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000564883

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Likely benign
(Dec 28, 2017)

germline

clinical testing

Citation Link,

SCV004803337

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Jan 15, 2024)

germline

clinical testing

PubMed (8)
[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	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

Diagnostic yield of exome sequencing in myopathies: Experience of a Slovenian tertiary centre.

Babić Božović I, Maver A, Leonardis L, Meznaric M, Osredkar D, Peterlin B.

PLoS One. 2021;16(6):e0252953. doi: 10.1371/journal.pone.0252953.

PubMed [citation]

PMID:: 34106991
PMCID:: PMC8189452

Non-dystrophic myotonias: clinical and mutation spectrum of 70 German patients.

Vereb N, Montagnese F, Gläser D, Schoser B.

J Neurol. 2021 May;268(5):1708-1720. doi: 10.1007/s00415-020-10328-1. Epub 2020 Dec 2.

PubMed [citation]

PMID:: 33263785
PMCID:: PMC8068660

See all PubMed Citations (8)

Details of each submission

From GeneDx, SCV000564883.4

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

Description

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004803337.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

Variant summary: CLCN1 c.501C>G (p.Phe167Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00086 in 1614204 control chromosomes in the gnomAD database, including 5 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in CLCN1 causing Myotonia congenita (0.00086 vs 0.0035), allowing no conclusion about variant significance. c.501C>G has been reported in the literature at a compound heterozygous state in individuals affected with autosomal recessive Myotonia congenita (examples, Gorukmez_2023, Bozovic_2021, Suetterlin_2022, Vereb_2020). It has also been reported at a heterozygous in several individuals with autosomal dominant Myotonia congenita and often along with a pathogenic variant from another gene that may fully explain the phenotype (example, Peddareddygari_2016, Maggi_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Myotonia congenita. Several publications report experimental evidence evaluating an impact on protein function. These results showed no damaging or marginal effect of this variant on the electrophysiological metrics of CLCN1 by whole-cell patch clamping in HEK293T cells or in xenopus oocytes (Desaphy_2013, Zhang_2000, Suetterlin_2022). The following publications have been ascertained in the context of this evaluation (PMID: 34106991, 23933576, 28993909, 27266866, 34529042, 10690989, 36964972). ClinVar contains an entry for this variant (Variation ID: 209138). Based on the evidence outlined above, the variant was classified as uncertain significance.

#	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: May 12, 2024

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