Submissions for variant NM_000083.3(CLCN1):c.854G>A (p.Gly285Glu)

gnomAD frequency: 0.00003  dbSNP: rs150885084

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000305463	SCV000329930	pathogenic	not provided	2022-04-17	criteria provided, single submitter	clinical testing	Observed in an affected mother and son with myotonia with presumed autosomal dominant inheritance (Thomas et al., 2008); Published functional studies demonstrate that the G285E variant leads to absent expression of chloride currents (Kubisch et al., 1998); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24037712, 15162127, 29606556, 18816629, 9736777, 11933197, 15786415, 18337730, 12390967, 29050397, 12210360, 22995991, 28662944, 12661046, 23810313, 31589614, 17932099, 34529042)
Athena Diagnostics Inc	RCV000305463	SCV000612800	pathogenic	not provided	2020-08-06	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant is primarily reported as autosomal recessive myotonia congenita (PMID: 9736777 15786415, 17932099, 18337730, 21387378, 24037712, 28662944), however, it has also been reported as autosomal dominant myotonia congenita (PMID: 18816629). Assessment of experimental evidence suggests this variant results in abnormal protein function. The variant causes loss of channel function as demonstrated by abrogation of chloride current (PMID 9736777). 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.
Invitae	RCV000560216	SCV000636300	pathogenic	Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 285 of the CLCN1 protein (p.Gly285Glu). This variant is present in population databases (rs150885084, gnomAD 0.01%). This missense change has been observed in individuals with autosomal recessive myotonia congenita (PMID: 9736777, 12390967, 18337730, 21387378, 24037712). ClinVar contains an entry for this variant (Variation ID: 280100). 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: 9736777). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000560216	SCV000893757	pathogenic	Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form	2022-02-14	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000305463	SCV001248204	pathogenic	not provided	2021-07-01	criteria provided, single submitter	clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV001753743	SCV001994821	pathogenic	Smith-Lemli-Opitz syndrome	2021-10-28	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000305463	SCV002017360	pathogenic	not provided	2021-09-29	criteria provided, single submitter	clinical testing
New York Genome Center	RCV000560216	SCV002506923	pathogenic	Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form	2021-04-16	criteria provided, single submitter	clinical testing	The c.854G>A (p.Gly285Glu) variant identified in the CLCN1 gene substitutes a well conserved Glycine for Glutamic Acid at amino acid 285/989 (exon 8/23). This variant is found with low frequency in gnomAD(v3.1.1) (5 heterozygotes, 0 homozygotes; allele frequency: 3.29e-5) suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be Damaging (SIFT; score:0.00) and Pathogenic (REVEL; score:0.93) to the function of the canonical transcript. This variant is reported as Pathogenic in ClinVar (VarID:280100) and has been identified in many affected individuals in the literature in homozygosity or compound heterozygosity with another variant [PMID:18337730; PMID: 24037712; others], and in some individuals with presumed autosomal recessive inheritance but without a second variant identified [PMID: 9736777; PMID:21387378; PMID: 24037712; others], as well as in one family with an affected mother and son and presumed autosomal dominant inheritance pattern [PMID:18816629]. Functional studies demonstrate the p.Gly285Glu variant leads to absence of chloride currents [PMID:9736777]. Given its identification in many affected individuals in the literature, functional studies showing deleterious effect, low frequency in population databases, and in silico algorithms prediction of a deleterious effect, the c.854G>A (p.Gly285Glu) variant identified in the CLCN1 gene is reported as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003409397	SCV004115388	pathogenic	CLCN1-related condition	2024-01-11	criteria provided, single submitter	clinical testing	The CLCN1 c.854G>A variant is predicted to result in the amino acid substitution p.Gly285Glu. This variant has been reported in patients with autosomal recessive myotonia congenita (see, for example, Kubisch et al. 1998. PubMed ID: 9736777; Trip et al. 2008. PubMed ID: 18337730). In addition, it has been documented in the heterozygous state among several individuals with presumed autosomal recessive disease (Kubisch et al. 1998. PubMed ID: 9736777, Tan et al. 2014. PubMed ID: 24037712) and in at least one affected mother and her son with presumed autosomal dominant inheritance (Thomas et al. 2008. PubMed ID: 18816629). Functional studies on this variant have demonstrated that it affects chloride channel function (Kubisch et al. 1998. PubMed ID: 9736777). Of note, c.854G is the first base of exon eight and therefore this change may be more likely to impact splicing; however, visual inspection of splicing in silico predictions does not indicate a large impact (Alamut Visual Plus v1.6.1). This variant is classified as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/280100/). This variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In summary, this variant is interpreted as pathogenic for autosomal recessive CLCN1-related disorders; however, it is uncertain in the context of an autosomal dominant mode of inheritance.
Mayo Clinic Laboratories, Mayo Clinic	RCV000305463	SCV004227073	pathogenic	not provided	2023-02-13	criteria provided, single submitter	clinical testing	PP1, PP3, PM2, PM3, PS3, PS4_moderate
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000305463	SCV002037481	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000305463	SCV002037847	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino	RCV003319192	SCV004023217	likely pathogenic	Tip-toe gait	2022-10-10	no assertion criteria provided	clinical testing