NM_000083.3(CLCN1):c.1283T>C (p.Phe428Ser) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 20, 2024
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000701519.5

Allele description [Variation Report for NM_000083.3(CLCN1):c.1283T>C (p.Phe428Ser)]

NM_000083.3(CLCN1):c.1283T>C (p.Phe428Ser)

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.1283T>C (p.Phe428Ser)

HGVS:

NC_000007.14:g.143332755T>C
NG_009815.1:g.21630T>C
NM_000083.3:c.1283T>CMANE SELECT
NP_000074.2:p.Phe428Ser
NP_000074.3:p.Phe428Ser
NC_000007.13:g.143029848T>C
NM_000083.2:c.1283T>C

Protein change:

F428S

Links:

dbSNP: rs774843953

NCBI 1000 Genomes Browser:

rs774843953

Molecular consequence:

NM_000083.3:c.1283T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Congenital myotonia, autosomal recessive form
Synonyms:: Myotonia congenita autosomal recessive; Becker disease; Myotonia generalized; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009715; MedGen: C0751360; Orphanet: 614; OMIM: 255700

Name:: Congenital myotonia, autosomal dominant form (THD)
Synonyms:: Myotonia congenita autosomal dominant; Thomsen disease; Thomsen's disease
Identifiers:: MONDO: MONDO:0008055; MedGen: C2936781; Orphanet: 614; OMIM: 160800

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000830322	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 20, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 12390967, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000830322

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 20, 2024)

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Novel CLCN1 mutations with unique clinical and electrophysiological consequences.

Wu FF, Ryan A, Devaney J, Warnstedt M, Korade-Mirnics Z, Poser B, Escriva MJ, Pegoraro E, Yee AS, Felice KJ, Giuliani MJ, Mayer RF, Mongini T, Palmucci L, Marino M, Rüdel R, Hoffman EP, Fahlke C.

Brain. 2002 Nov;125(Pt 11):2392-407.

PubMed [citation]

PMID:: 12390967

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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000830322.4

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

Description

This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 428 of the CLCN1 protein (p.Phe428Ser). This variant is present in population databases (rs774843953, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of autosomal recessive myotonia congenita (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 208083). 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 CLCN1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects CLCN1 function (PMID: 12390967). For these reasons, this variant has been classified as Pathogenic.

#	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: Oct 8, 2024

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