rs780834658

Positions:

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

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM5 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. R421C) has been classified as 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:5 U:2
• Conservation: PhyloP100: 6.86

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a intramembrane_region Helical (size 11) in uniprot entity CLCN1_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_000083.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-143332733-C-T is described in Lovd as [Pathogenic].
• 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 id is 447049.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=3, Likely_pathogenic=1}. Variant chr7-143332734-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCN1	NM_000083.3	c.1262G>A	p.Arg421His	missense_variant	12/23	ENST00000343257.7	NP_000074.3
CLCN1	NR_046453.2	n.1356+231G>A		intron_variant

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251448 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135896

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: 0.00000879

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

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000629

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.000138 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 22, 2022	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) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 29, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2017	- -

Congenital myotonia, autosomal recessive form Pathogenic:2

Pathogenic, no assertion criteria provided	research	Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences	Apr 06, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 02, 2023	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. -

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

Jan 29, 2024

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. -

CLCN1-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 06, 2023

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
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs780834658; hg19: chr7-143029827;