NM_000083.3:c.1453A>G

Variant names:

• chr7-143339304-A-G
• rs146457619
• NM_000083.3:c.1453A>G

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS3 PM1 PM5 PP2 PP5_Very_Strong

The NM_000083.3(CLCN1):​c.1453A>G​(p.Met485Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000604 in 1,613,142 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000329931: Published functional studies demonstrate variant leads to drastic reduction of single channel conductance, is strongly inwardly rectifying, and incompletely deactivates at negative voltages (Wollnik et al., 1997)" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M485K) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00063 (1 hom.)
• Consequence: CLCN1 NM_000083.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12 O:1
• Conservation: PhyloP100: 9.31
• Publications: 24 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: Pathogenic. The variant received 17 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000329931: Published functional studies demonstrate variant leads to drastic reduction of single channel conductance, is strongly inwardly rectifying, and incompletely deactivates at negative voltages (Wollnik et al., 1997);; SCV000612763: Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 9158157, 34529042); SCV000759744: Experimental studies have shown that this missense change affects CLCN1 function (PMID: 9158157).; SCV000915214: Functional studies involving expression in Xenopus oocytes demonstrated that the variant led to a drastic reduction of the single channel conductance compared to wildtype (Wollnik et al. 1997).; SCV004099583: "At least two publications report experimental evidence evaluating the variant in Xenopus oocytes and found that the variant severely impairs channel function, but does not exert a dominant negative effect when expressed with the wild type protein, consistent with it having an autosomal recessive mode of inheritance (e.g. Wollnik_1997, Suetterlin_2022)." PMID: 8533761, 34529042, 9158157; SCV004812552: An in vitro patch-clamp assay with limited validation in Xenopus oocytes demonstrates the variant causes a loss of chloride channel function and no dominant negative effect (PMID: 9158157).; SCV005362908: In vitro functional studies have demonstrated that this variant negatively impacts chloride channel function (Wollnik et al. 1997. PubMed ID: 9158157; Kubisch et al. 1998. PubMed ID: 9736777; Tan et al. 2013. PubMed ID: 24037712; Suetterlin et al. 2022. PubMed ID: 34529042).
• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000083.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-143339305-T-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2934639.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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.
• PP5: Variant 7-143339304-A-G is Pathogenic according to our data. Variant chr7-143339304-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 280101.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000083.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN1	NM_000083.3	MANE Select	c.1453A>G	p.Met485Val	missense	Exon 13 of 23	NP_000074.3	P35523
	CLCN1	NR_046453.2		n.1408A>G		non_coding_transcript_exon	Exon 12 of 22

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN1	ENST00000343257.7	TSL:1 MANE Select	c.1453A>G	p.Met485Val	missense	Exon 13 of 23	ENSP00000339867.2	P35523
	CLCN1	ENST00000432192.6	TSL:1	n.*738A>G		non_coding_transcript_exon	Exon 13 of 23	ENSP00000395949.2	H7C0N6
	CLCN1	ENST00000432192.6	TSL:1	n.*738A>G		3_prime_UTR	Exon 13 of 23	ENSP00000395949.2	H7C0N6

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

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: 0.000647

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000398 AC: 100 AN: 251490 AF XY: 0.000419

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000668

Gnomad OTH exome AF: 0.000651

GnomAD4 exome AF: 0.000626 AC: 915 AN: 1460812 Hom.: 1 Cov.: 31 AF XY: 0.000590 AC XY: 429 AN XY: 726794

African (AFR) AF: 0.0000897 AC: 3 AN: 33454

American (AMR) AF: 0.000783 AC: 35 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000762 AC: 847 AN: 1111018

Other (OTH) AF: 0.000497 AC: 30 AN: 60368

GnomAD4 genome AF: 0.000387 AC: 59 AN: 152330 Hom.: 0 Cov.: 32 AF XY: 0.000282 AC XY: 21 AN XY: 74492

African (AFR) AF: 0.000120 AC: 5 AN: 41562

American (AMR) AF: 0.000523 AC: 8 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.000647 AC: 44 AN: 68036

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

Alfa AF: 0.000647 Hom.: 0

Bravo AF: 0.000431

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000338 AC: 41

EpiCase AF: 0.000709

EpiControl AF: 0.000652

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	not provided (5)
3	-	-	Congenital myotonia, autosomal recessive form (4)
2	-	-	Congenital myotonia, autosomal recessive form;C2936781:Congenital myotonia, autosomal dominant form (2)
1	-	-	Batten-Turner congenital myopathy (1)
1	-	-	CLCN1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Pathogenic	0.36
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	0.19
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Uncertain	0.076	D
MutationAssessor	Benign	-0.060	N
PhyloP100		9.3
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-2.0	N
REVEL	Pathogenic	0.77
Sift	Benign	0.12	T
Sift4G	Benign	0.12	T
Polyphen		0.75	P
Vest4		0.93
MVP		0.90
MPC		0.46
ClinPred		0.065	T
GERP RS		5.6
Varity_R		0.57
gMVP		0.87
Mutation Taster		=12/88	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs146457619; hg19: chr7-143036397;