7-143341995-C-T

Variant names:

• chr7-143341995-C-T
• rs762754992
• NM_000083.3:c.1649C>T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM5 PP3_Strong PP5_Very_Strong

The NM_000083.3(CLCN1):​c.1649C>T​(p.Thr550Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T550R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: CLCN1 NM_000083.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 7.90

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 intramembrane_region Helical (size 32) in uniprot entity CLCN1_HUMAN there are 16 pathogenic changes around while only 0 benign (100%) in NM_000083.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-143341995-C-G is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966
• PP5: Variant 7-143341995-C-T is Pathogenic according to our data. Variant chr7-143341995-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 208084.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-143341995-C-T is described in Lovd as [Pathogenic]. Variant chr7-143341995-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCN1	NM_000083.3	c.1649C>T	p.Thr550Met	missense_variant	Exon 15 of 23	ENST00000343257.7	NP_000074.3
CLCN1	NR_046453.2	n.1604C>T		non_coding_transcript_exon_variant	Exon 14 of 22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCN1	ENST00000343257.7	c.1649C>T	p.Thr550Met	missense_variant	Exon 15 of 23	1	NM_000083.3	ENSP00000339867.2
CLCN1	ENST00000432192.6	n.*934C>T		non_coding_transcript_exon_variant	Exon 15 of 23	1		ENSP00000395949.2
CLCN1	ENST00000432192.6	n.*934C>T		3_prime_UTR_variant	Exon 15 of 23	1		ENSP00000395949.2
CLCN1	ENST00000650516.2	c.1649C>T	p.Thr550Met	missense_variant	Exon 15 of 23			ENSP00000498052.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251284 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135812

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: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461876 Hom.: 0 Cov.: 33 AF XY: 0.00000963 AC XY: 7 AN XY: 727242

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000363 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital myotonia, autosomal recessive form Pathogenic:2

Mar 03, 2022

Molecular Genetics, Royal Melbourne Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change in CLCN1 is predicted to replace threonine with methionine at codon 550, p.(Thr550Met). The threonine residue is highly conserved (100 vertebrates, UCSC), and is located in the P helix. There is a moderate physicochemical difference between threonine and methionine. The highest population minor allele frequency in gnomAD v2.1 is 0.003% (1/30,612 alleles) in the South Asian population, which is consistent with recessive disease. This variant has been detected in multiple individuals with myotonia, compound heterozygous for the variant and a pathogenic variant, and segregates with disease (PMID: 23113340, 25438602). This variant has also been reported in at least four probands with suspected dominantly inherited myotonia (PMID: 12390967, 24530047, 34790634, SCV000932923.3). Patch-clamp assays in human embryonic kidney cells showed hyperpolarization-induced gating steps and a dominant-negative effect indicating that this variant impacts protein function (PMID: 12390967). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PS3_Supporting, PM2_Supporting, PP1, PP3. -

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant p.T550M in CLCN1 (NM_000083.3) has been previously reported with both autosomal dominant as well as recessive myotonia congenita (Wu FF et al; Passeri E et al; Ivanova EA et al).Functional studies reveal a damaging effect (Wu FF et al). It has been submitted to ClinVar as Pathogenic. The p.T550M variant is observed in 1/30,612 (0.0033%) alleles from individuals of South Asian background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a moderate physicochemical difference between threonine and methionine. The p.T550M missense variant is predicted to be damaging by both SIFT and PolyPhen2. The threonine residue at codon 550 of CLCN1 is conserved in all mammalian species. The nucleotide c.1649 in CLCN1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Jul 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CLCN1: PM2, PM3, PM5, PS4:Moderate, PP3, PP4, PS3:Supporting -

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

Apr 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 550 of the CLCN1 protein (p.Thr550Met). This variant is present in population databases (rs762754992, gnomAD 0.003%). This missense change has been observed in individuals with both autosomal dominant and autosomal recessive myotonia congenita (PMID: 12390967, 23113340, 24530047, 25438602; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 208084). 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: 12390967). For these reasons, this variant has been classified as Pathogenic. -

Batten-Turner congenital myopathy Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.4	H
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MVP		0.99
MPC		0.75
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.93
gMVP		0.97

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: rs762754992; hg19: chr7-143039088; COSMIC: COSV58370401;