rs797045032

Variant names:

• chr7-143321720-GG-TC
• rs797045032
• NM_000083.3:c.568_569delGGinsTC
• CLCN1 p.Gly190Ser

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PS3 PM1 PM5 PP2 PP3 PP5

The NM_000083.3(CLCN1):​c.568_569delGGinsTC​(p.Gly190Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. The variant is present in control chromosomes in GnomAd MNV project. The variant allele was found at a frequency of 0.0000437 in 11 alleles, including 0 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV005039085: The variant results in a dramatic shift in voltage dependence of channel activation (Desaphy_2013). PMID:23933576" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G190R) has been classified as Likely pathogenic.

• Frequency: GnomAD MNV: 𝑓 0.000044 Genomes: not found (cov: 33)
• Consequence: CLCN1 NM_000083.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:13 U:1
• Conservation: PhyloP100: 10.0
• Publications: 22 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• myotonia congenita, autosomal recessive

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005039085: The variant results in a dramatic shift in voltage dependence of channel activation (Desaphy_2013). PMID:23933576; SCV005900427: Functional studies are supportive of a damaging effect on protein function (PMID: 23933576, 22521272, 34529042).; SCV000577243: Published electrophysiological studies in HEK293 cells showed a dramatic positive shift in voltage-dependent activation and highly reduced chloride currents (Desaphy et al., 2013); SCV000612791: "This variant was shown to impair channel function by reducing permeability, current density and affecting channel deactivation properties." PMID:22521272, PMID:23933576; SCV000649786: Experimental studies have shown that this missense change affects CLCN1 function (PMID: 22521272, 23933576).; SCV005362609: In vitro experimental studies suggest this variant affects protein function (Desaphy et al. 2013. PubMed ID: 23933576; Ulzi et al. 2012. PubMed ID: 2252127).
• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_000083.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-143321720-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 289004.
• 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: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 7-143321720-GG-TC is Pathogenic according to our data. Variant chr7-143321720-GG-TC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 209139.

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.568_569delGGinsTC	p.Gly190Ser	missense	N/A	NP_000074.3	P35523
	CLCN1	NR_046453.2		n.670_671delGGinsTC		non_coding_transcript_exon	Exon 5 of 22

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN1	ENST00000343257.7	TSL:1 MANE Select	c.568_569delGGinsTC	p.Gly190Ser	missense	N/A	ENSP00000339867.2	P35523
	CLCN1	ENST00000432192.6	TSL:1	n.334_335delGGinsTC		non_coding_transcript_exon	Exon 4 of 23	ENSP00000395949.2	H7C0N6
	CLCN1	ENST00000455478.6	TSL:1	n.22_23delGGinsTC		non_coding_transcript_exon	Exon 2 of 7	ENSP00000400027.2	H7C1F4

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

GnomAD MNV AF: 0.0000437 AC: 11 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
4	1	-	not provided (5)
3	-	-	Congenital myotonia, autosomal recessive form (3)
3	-	-	Congenital myotonia, autosomal recessive form;C2936781:Congenital myotonia, autosomal dominant form (3)
1	-	-	CLCN1-related disorder (1)
1	-	-	Congenital myotonia, autosomal dominant form (1)
1	-	-	Headache;C0026837:Rigidity;C0027051:Myocardial infarction;C0042571:Vertigo;C4022169:EMG: myotonic discharges;C4022683:Myotonia of the upper limb (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		10
Mutation Taster		=6/94	disease causing

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs797045032;

hg19: chr7-143018813;