7-143316395-A-T

Variant names:

• chr7-143316395-A-T
• rs202217420
• NM_000083.3:c.180+3A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PP3 PP5_Very_Strong

The NM_000083.3(CLCN1):​c.180+3A>T variant causes a splice region, intron change. The variant allele was found at a frequency of 0.000357 in 1,612,286 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (1 hom.)
• Consequence: CLCN1 NM_000083.3 splice_region, intron
• Scores: Splicing: ADA: 0.9989
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17
• Conservation: PhyloP100: 5.42
• Publications: 17 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 9 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 7-143316395-A-T is Pathogenic according to our data. Variant chr7-143316395-A-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 289967.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCN1	NM_000083.3	c.180+3A>T		splice_region_variant, intron_variant	Intron 1 of 22	ENST00000343257.7	NP_000074.3
CLCN1	NR_046453.2	n.282+3A>T		splice_region_variant, intron_variant	Intron 1 of 21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCN1	ENST00000343257.7	c.180+3A>T		splice_region_variant, intron_variant	Intron 1 of 22	1	NM_000083.3	ENSP00000339867.2
CLCN1	ENST00000650516.2	c.180+3A>T		splice_region_variant, intron_variant	Intron 1 of 22			ENSP00000498052.2

Frequencies

GnomAD3 genomes AF: 0.000269 AC: 41 AN: 152228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.000456

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000297 AC: 73 AN: 245822 AF XY: 0.000285

Gnomad AFR exome AF: 0.0000629

Gnomad AMR exome AF: 0.000348

Gnomad ASJ exome AF: 0.000301

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000200

Gnomad NFE exome AF: 0.000479

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000366 AC: 535 AN: 1459940 Hom.: 1 Cov.: 32 AF XY: 0.000336 AC XY: 244 AN XY: 726284

African (AFR) AF: 0.0000597 AC: 2 AN: 33476

American (AMR) AF: 0.000358 AC: 16 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.000230 AC: 6 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.000155 AC: 8 AN: 51692

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000436 AC: 485 AN: 1111862

Other (OTH) AF: 0.000298 AC: 18 AN: 60376

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152346 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74504

African (AFR) AF: 0.0000962 AC: 4 AN: 41578

American (AMR) AF: 0.000261 AC: 4 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000456 AC: 31 AN: 68036

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000384 Hom.: 0

Bravo AF: 0.000321

EpiCase AF: 0.000327

EpiControl AF: 0.000356

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital myotonia, autosomal recessive form Pathogenic:7

Nov 11, 2019

Institute of Human Genetics Munich, TUM University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 17, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene. There are no clear phenotype-genotype correlations; however, loss of function is generally associated with autosomal recessive inheritance (PMIDs: 20301529, 32117024). (I) 0108 - This gene is associated with both recessive and dominant disease. Recessive myotonia congenita (MIM#255700, Becker disease) is more severe than dominant myotonia congenita (MIM#160800, Thomsen disease). At least twelve variants were reported to cause both diseases (PMIDs: 20301529, 32010054). (I) 0112 - The condition associated with this gene has incomplete penetrance. Incomplete penetrance has been suggested for pathogenic variants associated with autosomal dominant inheritance (PMIDs: 20301529, 32117024). (I) 0115 - Variants in this gene are known to have variable expressivity. Intrafamilial phenotypic variability has been reported (PMID: 20301529). (I) 0212 - Non-canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (79 heterozygotes, 0 homozygotes). (SP) 0311 - An alternative nucleotide change at the nucleotide is present in gnomAD (v3) (1 heterozygote, 0 homozygotes). (I) 0508 - In silico predictions for abnormal splicing are conflicting. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar, and has been observed as homozygous or compound heterozgous in individuals with Becker disease/myotonia in the literature (PMIDs: 33263785, 31544778). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Nov 23, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 06, 2024

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.180+3A>T alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant weakens the canonical 5' splicing donor site. Nucleotide substitutions at this position, such as +3A>T and 3A>C have been confirmed by functional studies to result in exon skipping (PMID 19606495). The variant allele was found at a frequency of 0.0003 in 245822 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CLCN1 causing Myotonia congenita (0.0003 vs 0.0035), allowing no conclusion about variant significance. c.180+3A>T has been reported in the literature as a biallelic homozygous or compound heterozygous genotype in multiple individuals affected with Myotonia congenita (example, Mazon_2012). Loss of function is an established mechanism of Autosomal Recessive Myotonia congenita (Mazon_2012). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 22094069). ClinVar contains an entry for this variant (Variation ID: 289967). Based on the evidence outlined above, the variant was classified as pathogenic. -

Feb 20, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 20, 2021

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2 PP5 -

Jul 19, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:6

Apr 02, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CLCN1: PM3:Very Strong, PM2, PP1, BP4 -

Oct 24, 2024

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency of this variant in the general population is consistent with pathogenicity. (http://gnomad.broadinstitute.org) This variant has been reported in multiple families with autosomal recessive myotonia congenita. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Computational tools yielded predictions that this variant may interfere with normal RNA splicing. -

Apr 30, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP4, PM3_strong, PS4 -

Aug 02, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26502825, 24452722, 24515601, 23739125, 18337730, 24349310, 23810313, 18337100, 25065301, 24037712, 9040760, 28325641, 22094069, 25741868, 32117024, 31544778, 32655465, 29935101, 29606556, 28662944, 31589614, 33258288) -

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

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 1 of the CLCN1 gene. It does not directly change the encoded amino acid sequence of the CLCN1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs202217420, gnomAD 0.04%). This variant has been observed in individual(s) with autosomal recessive myotonia congenita (PMID: 9040760, 18337730, 22094069, 23810313, 24349310, 24515601). 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: 289967). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Mar 14, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital myotonia, autosomal dominant form Pathogenic:2

Jan 22, 2024

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PM3-strong, PP1 -

Dec 07, 2022

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	20
DANN	Benign	0.93
PhyloP100		5.4
PromoterAI		-0.14	Neutral
Mutation Taster		=6/94	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.88
SpliceAI score (max)		0.050		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: rs202217420; hg19: chr7-143013488;