rs767000881
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong
The NM_000083.3(CLCN1):c.1063G>A(p.Gly355Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000875 in 1,600,656 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a damaging outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G355E) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000083.3 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CLCN1 | NM_000083.3 | c.1063G>A | p.Gly355Arg | missense_variant, splice_region_variant | 9/23 | ENST00000343257.7 | |
CLCN1 | NR_046453.2 | n.1168G>A | splice_region_variant, non_coding_transcript_exon_variant | 9/22 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CLCN1 | ENST00000343257.7 | c.1063G>A | p.Gly355Arg | missense_variant, splice_region_variant | 9/23 | 1 | NM_000083.3 | P4 | |
CLCN1 | ENST00000432192.6 | c.*348G>A | splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant | 9/23 | 1 | ||||
CLCN1 | ENST00000650516.2 | c.1063G>A | p.Gly355Arg | missense_variant, splice_region_variant | 9/23 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152136Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251464Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135904
GnomAD4 exome AF: 0.00000828 AC: 12AN: 1448520Hom.: 0 Cov.: 30 AF XY: 0.0000111 AC XY: 8AN XY: 721488
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152136Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74310
ClinVar
Submissions by phenotype
Congenital myotonia, autosomal recessive form Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Dec 06, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | May 04, 2022 | The homozygous p.Gly355Arg variant in CLCN1 was identified by our study in 2 siblings with autosomal recessive myotonia congenita. The variant has been reported in at least 3 individuals of European and unknown ethnicity with autosomal recessive myotonia congenita (PMID: 20181190, 21221019, 9736066), and has been identified in 0.003% (1/34588) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs767000881). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 447043) as pathogenic by Athena Diagnostics Inc and Invitae. In vitro functional studies provide some evidence that the p.Gly355Arg variant may slightly impact protein function (PMID: 23933576). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in 1 affected homozygote, in combination with a reported variant of uncertain significance, and in at least 3 individuals with autosomal recessive myotonia congenita increases the likelihood that the p.Gly355Arg variant is pathogenic (VariationID: 209138; PMID: 9736066, 21221019). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM3, PP3, PS3_supporting (Richards 2015). - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | May 12, 2014 | - - |
Congenital myotonia, autosomal recessive form;C2936781:Congenital myotonia, autosomal dominant form Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 22, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 355 of the CLCN1 protein (p.Gly355Arg). This variant is present in population databases (rs767000881, gnomAD 0.003%). This missense change has been observed in individuals with autosomal recessive myotonia congenita (PMID: 19949657, 20181190, 21221019, 28427807; Invitae). ClinVar contains an entry for this variant (Variation ID: 447043). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CLCN1 function (PMID: 23933576). This variant disrupts the p.Gly355 amino acid residue in CLCN1. Other variant(s) that disrupt this residue have been observed in individuals with CLCN1-related conditions (PMID: 18337100), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at