NM_000083.3:c.763G>T
Variant summary
Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM5PP2PP3_ModeratePP5
The NM_000083.3(CLCN1):c.763G>T(p.Gly255Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,612,344 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. G255R) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000083.3 missense
Scores
Clinical Significance
Conservation
Publications
- myotonia congenita, autosomal dominantInheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
- myotonia congenita, autosomal recessiveInheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
- Thomsen and Becker diseaseInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Likely_pathogenic. The variant received 8 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152030Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.0000159 AC: 4AN: 251422 AF XY: 0.0000294 show subpopulations
GnomAD4 exome AF: 0.00000411 AC: 6AN: 1460314Hom.: 0 Cov.: 30 AF XY: 0.00000826 AC XY: 6AN XY: 726568 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152030Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74252 show subpopulations
ClinVar
Submissions by phenotype
not provided Pathogenic:1
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with 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 predict that this variant is damaging. -
Congenital myotonia, autosomal recessive form;C2936781:Congenital myotonia, autosomal dominant form Pathogenic:1
This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 255 of the CLCN1 protein (p.Gly255Trp). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individuals with autosomal recessive myotonia congenita (PMID: 29606556; Invitae). ClinVar contains an entry for this variant (Variation ID: 447070). 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) performed at Invitae indicates that this missense variant is expected to disrupt CLCN1 protein function with a positive predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Congenital myotonia, autosomal recessive form Pathogenic:1
PM2,PP3,PP2,PP5 -
not specified Uncertain:1
Variant summary: CLCN1 c.763G>T (p.Gly255Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251422 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.763G>T has been reported in the literature in a compound heterozygous individual affected with Myotonia congenita (Stunnenberg_2018). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 29606556). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at