rs780834658

Variant names:

• chr7-143332734-G-A
• rs780834658
• NM_000083.3:c.1262G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-143332734-G-A
• chr7-143332734-G-C
• chr7-143332734-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM5 PP2 PP3_Moderate PP5

The NM_000083.3(CLCN1):​c.1262G>A​(p.Arg421His) variant causes a missense change. The variant allele was found at a frequency of 0.00000752 in 1,461,796 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. R421L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: CLCN1 NM_000083.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:2
• Conservation: PhyloP100: 6.86
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• myotonia congenita, autosomal dominant

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• myotonia congenita, autosomal recessive

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Thomsen and Becker disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000083.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-143332734-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 585678.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 106 curated pathogenic missense variants (we use a threshold of 10). The gene has 18 curated benign missense variants. Gene score misZ: 0.21191 (below the threshold of 3.09). Trascript score misZ: 0.95247 (below the threshold of 3.09). GenCC associations: The gene is linked to myotonia congenita, autosomal dominant, myotonia congenita, autosomal recessive, Thomsen and Becker disease.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.851
• PP5: Variant 7-143332734-G-A is Pathogenic according to our data. Variant chr7-143332734-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 447049.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCN1	NM_000083.3	c.1262G>A	p.Arg421His	missense_variant	Exon 12 of 23	ENST00000343257.7	NP_000074.3
CLCN1	NR_046453.2	n.1356+231G>A		intron_variant	Intron 11 of 21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCN1	ENST00000343257.7	c.1262G>A	p.Arg421His	missense_variant	Exon 12 of 23	1	NM_000083.3	ENSP00000339867.2
CLCN1	ENST00000432192.6	n.*547G>A		non_coding_transcript_exon_variant	Exon 12 of 23	1		ENSP00000395949.2
CLCN1	ENST00000432192.6	n.*547G>A		3_prime_UTR_variant	Exon 12 of 23	1		ENSP00000395949.2
CLCN1	ENST00000650516.2	c.1262G>A	p.Arg421His	missense_variant	Exon 12 of 23			ENSP00000498052.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251448 AF XY: 0.00000736

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000752 AC: 11 AN: 1461796 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727220

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 0.00000629 AC: 7 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000719 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2 Uncertain:1

May 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 29, 2017

Athena Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 22, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21221019, 25065301, 28427807, 27118449) -

Congenital myotonia, autosomal recessive form;C2936781:Congenital myotonia, autosomal dominant form Pathogenic:2

Jan 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 421 of the CLCN1 protein (p.Arg421His). This variant is present in population databases (rs780834658, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal recessive myotonia congenita (PMID: 21221019, 35907044). 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: 447049). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CLCN1 protein function. This variant disrupts the p.Arg421 amino acid residue in CLCN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22094069, 23113340, 23739125). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

May 28, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital myotonia, autosomal recessive form Pathogenic:2

Apr 06, 2022

Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Nov 02, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CLCN1 c.1262G>A (p.Arg421His) results in a non-conservative amino acid change located in a Chloride channel, voltage gated domain (IPR001807) of the encoded protein sequence. This alters a highly conserved residue (HGMD) in which another missense change (p.Arg421Cys) is classified as pathogenic. 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 8e-06 in 251448 control chromosomes (gnomAD). c.1262G>A has been reported in the literature in multiple individuals affected with Myotonia congenita (Modoni_2011, Ferradini_2017, Yuan_2022), and some were reported as compound heterozygous with other pathogenic variants. These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 21221019, 25065301, 28427807, 35907044). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic (n=2), likely pathogenic (n=1), or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

CLCN1-related disorder Uncertain:1

Sep 06, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CLCN1 c.1262G>A variant is predicted to result in the amino acid substitution p.Arg421His. This variant has been reported with a second CLCN1 loss-of-function variant in two family members with autosomal recessive myotonia congenita (Table 1, Modoni et al. 2011. PubMed ID: 21221019). Of note, a different amino acid change at this position (p.Arg421Cys) has been reported with a second CLCN1 variant in at least four individuals with autosomal recessive myotonia congenita (Mazón et al. 2011. PubMed ID: 22094069; Suetterlin et al. 2022. PubMed ID: 34529042; Morrow et al. 2013. PubMed ID: 23810313). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-143029827-G-A). Although we suspect that this variant may be pathogenic autosomal recessive myotonia congenita at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Benign	1.2	L
PhyloP100		6.9
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-2.0	N
REVEL	Pathogenic	0.68
Sift	Benign	0.57	T
Sift4G	Benign	0.58	T
Polyphen		1.0	D
Vest4		0.89
MutPred		0.48		Gain of relative solvent accessibility (P = 0.0479);
MVP		0.97
MPC		0.82
ClinPred		0.91	D
GERP RS		5.4
Varity_R		0.35
gMVP		0.75
Mutation Taster		=14/86	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs780834658; hg19: chr7-143029827;