rs375596425

chr7-143339323-G-A

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PP3_Strong PP5_Very_Strong

The NM_000083.3(CLCN1):c.1471+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000292 in 1,610,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000032 (0 hom.)
• Consequence: CLCN1 NM_000083.3 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 9.99

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 20 ACMG points.

• PVS1: Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• 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 7-143339323-G-A is Pathogenic according to our data. Variant chr7-143339323-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 447052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-143339323-G-A is described in Lovd as [Likely_pathogenic]. Variant chr7-143339323-G-A is described in Lovd as [Pathogenic]. Variant chr7-143339323-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLCN1	NM_000083.3	c.1471+1G>A		splice_donor_variant		ENST00000343257.7
CLCN1	NR_046453.2	n.1426+1G>A		splice_donor_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLCN1	ENST00000343257.7	c.1471+1G>A		splice_donor_variant		1	NM_000083.3	P4
CLCN1	ENST00000432192.6	c.*756+1G>A		splice_donor_variant, NMD_transcript_variant		1
CLCN1	ENST00000650516.2	c.1471+1G>A		splice_donor_variant				A2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152218 Hom.: 0 Cov.: 32

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251488 Hom.: 1 AF XY: 0.0000294 AC XY: 4 AN XY: 135918

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: 0.0000440

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000315 AC: 46 AN: 1458658 Hom.: 0 Cov.: 31 AF XY: 0.0000386 AC XY: 28 AN XY: 725956

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: 0.0000397

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152218 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74360

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: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000192 Hom.: 0

Bravo AF: 0.0000113

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 17, 2020	PVS1, PS4_moderate, PM2, PM3 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 27, 2021	In families where this variant has been associated with autosomal recessive inheritance, c. 1471+1 G>A has been identified as heterozygous variant in unaffected parents (Meyer-Kleine et al., 1995; Ronstedt et al., 2015); however, information about families with myotonia who only harbor the c.1471+1 G>A variant is limited.; Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 24452722, 25065301, 27614575, 18337100, 31589614, 33304817, 8533761, 26502825) -
Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Oct 28, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 08, 2019	- -

Congenital myotonia, autosomal recessive form Pathogenic:3

Likely pathogenic, criteria provided, single submitter	research	Department Of Human Genetics, Institute Of Clinical And Translational Research, Biomedical Research Center, Slovak Academy Of Sciences	-	The c.1471+1G>A (p.?) variant was found in a heterozygous state in 1 Slovak patient with Myotonia congenita, who carried another two Likely pathogenic variants in cis: [c.905A>G; c.1295C>A]. The c.1471+1G>A variant is listed as a disease-causing in the HGMD database (CS951379). GnomAD Exomes Version: 4.0 indicates the frequency of f = 0.0000315. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 20, 2024	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	May 02, 2023	The heterozygous c.1471+1G>A variant in CLNC1 was identified by our study, in the compound heterozygous state along with a variant of uncertain significance (NC_000007.14:g.143339511G>A), in one individual with congenital myotonia. This individual also carried a variant of uncertain significance (NC_000007.14:g.143339511G>A), however the phase of these variants are unknown at this time. The c.1471+1G>A variant in CLNC1 has been previously reported in 12 unrelated individuals with autosomal recessive myotonia congenita (PMID: 33304817, PMID: 25438602, PMID: 22094069, PMID: 27614575, PMID: 31544778, PMID: 25065301, PMID: 22521272, PMID: 24349310, PMID: 8533761) but has been identified in 0.001% (1/68044) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs375596425). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 447052) and has been interpreted as pathogenic or likely pathogenic by multiple submitters. Of these 12 previously reported affected unrelated individuals, 1 was a homozygote (PMID: 27614575), six were compound heterozygotes who carried pathogenic or likely pathogenic variants in trans (PMID: 22094069, ClinVar Variation ID: 289967; PMID: 27614575, PMID: 24349310, PMID: 8533761, ClinVar Variation ID: 17545), one was a compound heterozygote who carried a pathogenic variant in unknown phase (PMID: 25438602, ClinVar Variation ID: 17545; ), and two were compound heterozygotes who carried variants of uncertain significance in trans (PMID: 31544778, ClinVar Variation ID: 209138, 1013567; PMID: 25065301), which increases the likelihood that the c.1471+1G>A variant is pathogenic. RT-PCR analysis performed on RNA from affected tissue showed evidence of exon skipping of exon 13 (PMID: 17932099). This variant is located in the 5' splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. Loss of function is an established disease mechanism of autosomal recessive myotonia congenita. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive myotonia congenita. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PS3_Supporting, PM3_VeryStrong (Richards 2015). -

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

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 18, 2023	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 447052). Disruption of this splice site has been observed in individual(s) with myotonia congenita (PMID: 8533761, 22094069, 22521272, 24349310, 27614575). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs375596425, gnomAD 0.008%), including at least one homozygous and/or hemizygous individual. This sequence change affects a donor splice site in intron 13 of the CLCN1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CLCN1 are known to be pathogenic (PMID: 17932099, 22094069, 23739125). -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 14, 2022	- -

Congenital myotonia, autosomal dominant form Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Apr 04, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.43
Cadd	Pathogenic	33
Dann	Uncertain	1.0
Eigen	Pathogenic	1.3
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D
GERP RS		5.6

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.93		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.93		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs375596425; hg19: chr7-143036416;