rs121912801

Positions:

chr7-143339527-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PP3_StrongPP5_Very_Strong

The NM_000083.3(CLCN1):c.1488G>T(p.Arg496Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,613,452 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 Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

CLCN1
NM_000083.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 0.692

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a mutagenesis_site Changed gating of the channel. (size 0) in uniprot entity CLCN1_HUMAN

PP3

MetaRNN computational evidence supports a deleterious effect, 0.986

PP5

Variant 7-143339527-G-T is Pathogenic according to our data. Variant chr7-143339527-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 17535.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-143339527-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCN1	NM_000083.3 linkuse as main transcript	c.1488G>T	p.Arg496Ser	missense_variant	14/23	ENST00000343257.7	NP_000074.3
CLCN1	NR_046453.2 linkuse as main transcript	n.1443G>T		non_coding_transcript_exon_variant	13/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
CLCN1	ENST00000343257.7 linkuse as main transcript	c.1488G>T	p.Arg496Ser	missense_variant	14/23	1	NM_000083.3	ENSP00000339867	P4
CLCN1	ENST00000432192.6 linkuse as main transcript	c.*773G>T		3_prime_UTR_variant, NMD_transcript_variant	14/23	1		ENSP00000395949
CLCN1	ENST00000650516.2 linkuse as main transcript	c.1488G>T	p.Arg496Ser	missense_variant	14/23			ENSP00000498052	A2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251466

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1461306

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727006

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000671

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:

0.0000198

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 02, 2024	Published functional studies demonstrate a damaging effect; specifically, cRNA expressed in Xenopus oocytes did not yield detectable currents, suggesting that the variant results in loss of ion channel function. Additionally, co-expression studies with wild type channel yielded detectable, though reduced currents, suggesting that the variant does not impact wild type channel function and is consistent with recessive inheritance (PMID: 7951242); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26502825, 31589614, 7951242, 8533761, 23739125, 27199537, 22094069, 33263785) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 28, 2019	- -

Congenital myotonia, autosomal recessive form

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 19, 2022	Variant summary: CLCN1 c.1488G>T (p.Arg496Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251466 control chromosomes (gnomAD). c.1488G>T has been reported in the literature in the homozygous and compound heterozygous state in many individuals affected with the autosomal recessive form of congenital myotonia, Becker disease (e.g. Lorenz_1994, Mazon_2012, Brugnoni_2013, Ronstedt_2015, Stunnenberg_2018, Vereb_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. When expressed in vitro, the variant protein did not give rise to currents above levels observed in cells without CLCN1 expression (e.g. Lorenz_1994). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 1994	- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 14, 2023

This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 496 of the CLCN1 protein (p.Arg496Ser). This variant is present in population databases (rs121912801, gnomAD 0.006%). This missense change has been observed in individual(s) with autosomal recessive myotonia congenita (PMID: 7951242, 22094069, 26502825, 27199537). 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: 17535). 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: 7951242, 8533761). For these reasons, this variant has been classified as Pathogenic. -

CLCN1-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 09, 2023

The CLCN1 c.1488G>T variant is predicted to result in the amino acid substitution p.Arg496Ser. This variant, along with a second variant or in the homozygous state, was reported in several individuals with myotonia congenita (see, for example, Lorenz et al 1994. PubMed ID: 7951242; Mazón et al 2011. PubMed ID: 22094069; Vereb et al 2020. PubMed ID: 33263785). Of note, heterozygous individuals have been reported to be unaffected suggesting this variant exhibits autosomal recessive inheritance (Mazón et al 2011. PubMed ID: 22094069). In vitro experimental studies suggest this variant impacts protein function (Lorenz et al 1994. PubMed ID: 7951242). This variant is reported in 0.0056% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-143036620-G-T). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.43

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.87

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Benign

0.44

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.63

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.88

MutationAssessor

Pathogenic

3.9

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-5.5

REVEL

Pathogenic

0.73

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Polyphen

0.38

Vest4

0.98

MutPred

0.88

Loss of methylation at R496 (P = 0.007);

MVP

0.94

MPC

0.79

ClinPred

0.97

GERP RS

2.9

Varity_R

0.98

gMVP

0.98

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over