rs756199349

Variant names:

• chr7-143332483-G-T
• rs756199349
• NM_000083.3:c.1231G>T

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000083.3(CLCN1):​c.1231G>T​(p.Gly411Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G411G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CLCN1 NM_000083.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 9.59
• Publications: 3 publications found

Genes affected

CLCN1 (HGNC:2019): (chloride voltage-gated channel 1) The CLCN family of voltage-dependent chloride channel genes comprises nine members (CLCN1-7, Ka and Kb) which demonstrate quite diverse functional characteristics while sharing significant sequence homology. The protein encoded by this gene regulates the electric excitability of the skeletal muscle membrane. Mutations in this gene cause two forms of inherited human muscle disorders: recessive generalized myotonia congenita (Becker) and dominant myotonia (Thomsen). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2012]

CLCN1 Gene-Disease associations (from GenCC):

• myotonia congenita, autosomal dominant

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• myotonia congenita, autosomal recessive

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Thomsen and Becker disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000083.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 106 curated pathogenic missense variants (we use a threshold of 10). The gene has 18 curated benign missense variants. Gene score misZ: 0.21191 (below the threshold of 3.09). Trascript score misZ: 0.95247 (below the threshold of 3.09). GenCC associations: The gene is linked to myotonia congenita, autosomal dominant, myotonia congenita, autosomal recessive, Thomsen and Becker disease.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973
• PP5: Variant 7-143332483-G-T is Pathogenic according to our data. Variant chr7-143332483-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 429659.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCN1	NM_000083.3	c.1231G>T	p.Gly411Cys	missense_variant	Exon 11 of 23	ENST00000343257.7	NP_000074.3
CLCN1	NR_046453.2	n.1336G>T		non_coding_transcript_exon_variant	Exon 11 of 22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCN1	ENST00000343257.7	c.1231G>T	p.Gly411Cys	missense_variant	Exon 11 of 23	1	NM_000083.3	ENSP00000339867.2
CLCN1	ENST00000432192.6	n.*516G>T		non_coding_transcript_exon_variant	Exon 11 of 23	1		ENSP00000395949.2
CLCN1	ENST00000432192.6	n.*516G>T		3_prime_UTR_variant	Exon 11 of 23	1		ENSP00000395949.2
CLCN1	ENST00000650516.2	c.1231G>T	p.Gly411Cys	missense_variant	Exon 11 of 23			ENSP00000498052.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461724 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727180

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111856

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Dec 20, 2023

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been identified in at least one individual with autosomal recessive myotonia congenita. This variant has not been reported in large, multi-ethnic general populations. (http://gnomad.broadinstitute.org) Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 33013670) In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. -

Mar 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 14, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect and show that this variant abolishes chloride currents and significantly reduces plasma membrane protein expression (PMID: 33013670); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29606556, 33013670) -

Congenital myotonia, autosomal recessive form Pathogenic:2

-

Department Of Human Genetics, Institute Of Clinical And Translational Research, Biomedical Research Center, Slovak Academy Of Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The c.1231G>T (p.(Gly411Cys)) variant was found in a heterozygous state in 1 Slovak patient with Myotonia congenita, who carried also heterozygous Likely pathogenic variant c.2680C>T. The c.1231G>T variant is listed as a disease-causing in the HGMD database (CM187251) and it has been published for the first time in PMID: 29606556. GnomAD Exomes Version: 4.0 indicates the frequency of f = 0.00000318. When transfected into HEK293 cells, the variant did not properly traffick to the cell surface. When these transfected cells were treated with MG132, the trafficking defect was rescued but cells expressing the variant still failed to produce a chloride current when examined via patch-clamp analysis, indicating the variant produces a non-functional chloride channel (PMID: 33013670) -

Jun 27, 2023

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CLCN1 c.1231G>T (p.Gly411Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251470 control chromosomes (gnomAD). c.1231G>T has been reported in the literature in compound heterozygous individuals affected with Autosomal Recessive Myotonia Congenita (e.g. Stunnenberg_2018, Altamura_2020). These data indicate that the variant may be associated with disease. When transfected into HEK293 cells, the variant did not properly traffick to the cell surface. When these transfected cells were treated with MG132, the trafficking defect was rescued but cells expressing the variant still failed to produce a chloride current when examined via patch-clamp analysis, indicating the variant produces a non-functional chloride channel (Altamura_2020). The following publications have been ascertained in the context of this evaluation (PMID: 33013670, 29606556). Three ClinVar submitters have assessed the variant since 2014: two classified the variant as uncertain significance and one as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Congenital myotonia, autosomal recessive form;C2936781:Congenital myotonia, autosomal dominant form Pathogenic:1

May 08, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense change has been observed in individual(s) with autosomal recessive myotonic congenita (PMID: 29606556, 33013670; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 411 of the CLCN1 protein (p.Gly411Cys). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 429659). 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. Experimental studies have shown that this missense change affects CLCN1 function (PMID: 33013670). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		9.6
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-8.6	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.80		Loss of disorder (P = 0.0727);
MVP		0.99
MPC		0.76
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.97
gMVP		0.90
Mutation Taster		=17/83	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs756199349; hg19: chr7-143029576;