rs774396430

Variant names:

Variant summary

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

The NM_000083.3(CLCN1):c.979G>A(p.Val327Ile) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000044 in 1,614,058 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

CLCN1
NM_000083.3 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 5.89

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 topological_domain Extracellular (size 25) in uniprot entity CLCN1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000083.3

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 7-143330897-G-A is Pathogenic according to our data. Variant chr7-143330897-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 447078.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-143330897-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCN1	NM_000083.3 link	c.979G>A	p.Val327Ile	missense_variant, splice_region_variant	Exon 8 of 23	ENST00000343257.7	NP_000074.3	P35523
CLCN1	NR_046453.2 link	n.1084G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 8 of 22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCN1	ENST00000343257.7 link	c.979G>A	p.Val327Ile	missense_variant, splice_region_variant	Exon 8 of 23	1	NM_000083.3	ENSP00000339867.2		P35523

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152178

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251448

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135894

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000465

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

727240

show subpopulations

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:

0.0000594

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74330

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000324

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Oct 01, 2021

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 04, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1, PP3, PP4, PM2_moderate, PM3, PS4 -

Dec 20, 2015

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 01, 2020

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Non-canonical splice variant located at the last nucleotide of an exon in a gene for which loss-of-function is a known mechanism of disease, and both splice predictors and evolutionary conservation support a deleterious effect, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Expression of V327I cRNA into Xenopus oocytes yielded CLC-1 currents that were indistinguishable from wild type, which supports the hypothesis that the c.979 G>A variant exerts its effect by affecting splicing (Lorenz et al., 1994); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 32670189, 23810313, 7951242, 11840191, 32010054, 8533761, 15786415, 24037712, 21387378, 22187529, 23516313, 17932099, 11933197) -

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

Pathogenic:2

Nov 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 327 of the CLCN1 protein (p.Val327Ile). This variant also falls at the last nucleotide of exon 8, which is part of the consensus splice site for this exon. This variant is present in population databases (rs774396430, gnomAD 0.003%). This missense change has been observed in individuals with autosomal recessive myotonia congenita (PMID: 7951242, 11840191, 23516313, 23810313). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 447078). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Apr 13, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CLCN1-related disorder

Pathogenic:1

Jun 06, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CLCN1 c.979G>A variant is predicted to result in the amino acid substitution p.Val327Ile. This variant affects the last nucleotide of exon 8 and is predicted to impact splicing according to a splicing prediction software (Splice AI, Jaganathan K, et al. 2019. PubMed ID: 30661751). This variant has been reported in multiple individuals with autosomal recessive myotonia congenita (Horga et al. 2013. PubMed ID: 23516313; Meyer et al. 2020. PubMed ID: 32670189; Vereb et al. 2020. PubMed ID: 33263785; Suetterlin et al. 2022. PubMed ID: 34529042; Vivekanandam et al. 2023. PubMed ID: 36796140; Lorenz et al. 1994. PubMed ID: 7951242; Fialho et al. 2007. PubMed ID: 17932099; Sun et al. 2001. PubMed ID: 11840191; Morrow et al. 2013. PubMed ID: 23810313). This variant is reported in 0.0031% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Congenital myotonia, autosomal recessive form

Pathogenic:1

Jul 16, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene. There are no clear phenotype-genotype correlations, however loss of function is generally associated with autosomal recessive inheritance (PMIDs: 20301529, 32117024). (I) 0108 - This gene is associated with both recessive and dominant disease. Recessive myotonia congenita (MIM#255700, Becker disease) is more severe than dominant myotonia congenita (MIM#160800, Thomsen disease). At least twelve variants were reported to cause both diseases (PMIDs: 20301529, 32010054). (I) 0112 - The condition associated with this gene has incomplete penetrance. Incomplete penetrance has been suggested for pathogenic variants associated with autosomal dominant inheritance (PMIDs: 20301529, 32117024). (I) 0115 - Variants in this gene are known to have variable expressivity. Intrafamilial phenotypic variability has been reported (PMID: 20301529). (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to isoleucine. The variant is also in a splice region as it affects the last coding base of an exon. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (4 heterozygotes, 0 homozygotes). (SP) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. However, this nucleotide is highly conserved and abnormal splicing is predicted by in silico tools. (I) 0600 - Variant is located in the annotated voltage gated chloride channel (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic and likely pathogenic by clinical laboratories in ClinVar, and has been observed as compound heterozygous in at least five unrelated individuals in the literature (PMIDs: 32670189, 33263785, 11840191, 7951242, 21387378). (SP) 1010 - Functional evidence for this variant is inconclusive. Patch clamp studies have shown that this variant does not affect the chloride channel current (PMID: 7951242). However, patch clamp assays have been shown to be unreliable, therefore results from these studies are used with caution during variant classification. (I) 1101 - Very strong and specific phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.12

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.047

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.77

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.35

MetaSVM

Uncertain

0.029

MutationAssessor

Benign

1.5

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.86

REVEL

Uncertain

0.61

Sift

Uncertain

0.018

Sift4G

Uncertain

0.022

Polyphen

0.18

Vest4

0.26

MVP

0.88

MPC

0.17

ClinPred

0.47

GERP RS

3.8

Varity_R

0.39

gMVP

0.42

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.88

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.88

Position offset: 0

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