rs777685454

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM5PP3_StrongPP5

The NM_000083.3(CLCN1):c.1606G>A(p.Val536Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,613,744 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V536A) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

CLCN1
NM_000083.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 9.99

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 Likely_pathogenic. Variant got 9 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000083.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-143341953-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2926032.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.974

PP5

Variant 7-143341952-G-A is Pathogenic according to our data. Variant chr7-143341952-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 447054.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=2, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLCN1	NM_000083.3 linkuse as main transcript	c.1606G>A	p.Val536Ile	missense_variant	15/23	ENST00000343257.7
CLCN1	NR_046453.2 linkuse as main transcript	n.1561G>A		non_coding_transcript_exon_variant	14/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
CLCN1	ENST00000343257.7 linkuse as main transcript	c.1606G>A	p.Val536Ile	missense_variant	15/23	1	NM_000083.3	P4
CLCN1	ENST00000432192.6 linkuse as main transcript	c.*891G>A		3_prime_UTR_variant, NMD_transcript_variant	15/23	1
CLCN1	ENST00000650516.2 linkuse as main transcript	c.1606G>A	p.Val536Ile	missense_variant	15/23			A2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152198

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:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251390

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.0000616

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:

0.0000924

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1461546

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727084

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.0000180

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74358

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:

0.000188

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000425

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 19, 2023	Reported in a heterozygous state in an individual with a personal and family history of myotonia congenita (PMID: 28325641); Reported in patients with myotonia who also harbored as second CLCN1 variant, phase unknown (PMID: 23152584, 34529042); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23152584, 31589614, 29405036, 34529042, 24304580, 28325641) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 07, 2016	- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 536 of the CLCN1 protein (p.Val536Ile). This variant is present in population databases (rs777685454, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive myotonia congenita and late onset myotonia (PMID: 23152584, 29405036; 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: 447054). 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%. This variant disrupts the p.Val536 amino acid residue in CLCN1. Other variant(s) that disrupt this residue have been observed in individuals with CLCN1-related conditions (PMID: 24304580), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Congenital myotonia, autosomal recessive form

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

The CLCN1 c.1606G>A (p.Val536Ile) variant has been observed in individuals with autosomal recessive myotonia congenita and late onset myotonia (Raheem O et al, Ferese R et al). This p.Val536Ile variant has allele frequency of 0.002829% in the gnomAD and novel (not in any individuals) in 1000 genome database. It has been submitted to ClinVar with varying interpretations: Pathogenic/ Likely Pathogenic. The amino acid Val at position 536 is changed to a Ile changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Val536Ile in CLCN1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.55

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.97

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.56

MetaRNN

Pathogenic

0.97

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.0

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-0.82

REVEL

Pathogenic

0.67

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0060

Polyphen

1.0

Vest4

0.90

MutPred

0.85

Loss of sheet (P = 0.0817);

MVP

0.97

MPC

0.66

ClinPred

0.69

GERP RS

5.9

Varity_R

0.68

gMVP

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

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