7-143332483-G-T

Position:

• chr7-143332483-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 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:4 U:1
• Conservation: PhyloP100: 9.59

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000083.3
• PM2: Very rare variant in population databases, with high coverage
• 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. Variant chr7-143332483-G-T is described in Lovd as [Pathogenic]. Variant chr7-143332483-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLCN1	NM_000083.3	c.1231G>T	p.Gly411Cys	missense_variant	11/23	ENST00000343257.7
CLCN1	NR_046453.2	n.1336G>T		non_coding_transcript_exon_variant	11/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLCN1	ENST00000343257.7	c.1231G>T	p.Gly411Cys	missense_variant	11/23	1	NM_000083.3	P4
CLCN1	ENST00000432192.6	c.*516G>T		3_prime_UTR_variant, NMD_transcript_variant	11/23	1
CLCN1	ENST00000650516.2	c.1231G>T	p.Gly411Cys	missense_variant	11/23			A2

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital myotonia, autosomal recessive form Pathogenic:2

Likely pathogenic, criteria provided, single submitter	research	Department Of Human Genetics, Institute Of Clinical And Translational Research, Biomedical Research Center, Slovak Academy Of Sciences	-	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) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 27, 2023	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. -

not provided Pathogenic:1 Uncertain:1

Uncertain significance, flagged submission	clinical testing	GeneDx	Dec 22, 2017	The G411C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The G411C variant is not observed in large population cohorts (Lek et al., 2016). The G411C 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. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Missense variants in nearby residues have been reported in the Human Gene Mutation Database in individuals with myotonia (Stenson et al., 2014). Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2019	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 08, 2023

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CLCN1 function (PMID: 33013670). 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. ClinVar contains an entry for this variant (Variation ID: 429659). 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 variant is not present in population databases (gnomAD no frequency). 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). -

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
MutationTaster	Benign	1.0	D
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs756199349; hg19: chr7-143029576;