ClinVar Genomic variation as it relates to human health

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene. There are no clear phenotype-genotype correlations, however loss of function is generally associated with autosomal recessive inheritance (PMIDs: 20301529, 32117024). (I) 0108 - This gene is associated with both recessive and dominant disease. Recessive myotonia congenita (MIM#255700, Becker disease) is more severe than dominant myotonia congenita (MIM#160800, Thomsen disease). At least twelve variants were reported to cause both diseases (PMIDs: 20301529, 32010054). (I) 0112 - The condition associated with this gene has incomplete penetrance. Incomplete penetrance has been suggested for pathogenic variants associated with autosomal dominant inheritance (PMIDs: 20301529, 32117024). (I) 0115 - Variants in this gene are known to have variable expressivity. Intrafamilial phenotypic variability has been reported (PMID: 20301529). (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to isoleucine. The variant is also in a splice region as it affects the last coding base of an exon. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (4 heterozygotes, 0 homozygotes). (SP) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. However, this nucleotide is highly conserved and abnormal splicing is predicted by in silico tools. (I) 0600 - Variant is located in the annotated voltage gated chloride channel (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic and likely pathogenic by clinical laboratories in ClinVar, and has been observed as compound heterozygous in at least five unrelated individuals in the literature (PMIDs: 32670189, 33263785, 11840191, 7951242, 21387378). (SP) 1010 - Functional evidence for this variant is inconclusive. Patch clamp studies have shown that this variant does not affect the chloride channel current (PMID: 7951242). However, patch clamp assays have been shown to be unreliable, therefore results from these studies are used with caution during variant classification. (I) 1101 - Very strong and specific phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

PP1, PP3, PP4, PM2_moderate, PM3, PS4

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 327 of the CLCN1 protein (p.Val327Ile). This variant also falls at the last nucleotide of exon 8, which is part of the consensus splice site for this exon. This variant is present in population databases (rs774396430, gnomAD 0.003%). This missense change has been observed in individuals with autosomal recessive myotonia congenita (PMID: 7951242, 11840191, 23516313, 23810313). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 447078). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

Expression of V327I cRNA into Xenopus oocytes yielded CLC-1 currents that were indistinguishable from wild type, which supports the hypothesis that the c.979 G>A variant exerts its effect by affecting splicing (PMID: 7951242); Not observed at significant frequency in large population cohorts (gnomAD); Alters the last nucleotide of the exon and is predicted to damage the splice donor site but the effect on protein function is unclear; This variant is associated with the following publications: (PMID: 17932099, 11933197, 23516313, 22187529, 21387378, 24037712, 15786415, 8533761, 32010054, 11840191, 23810313, 32670189, 33263785, 34529042, 7951242, 32117024, 36796140)

The CLCN1 c.979G>A variant is predicted to result in the amino acid substitution p.Val327Ile. This variant affects the last nucleotide of exon 8 and is predicted to impact splicing according to a splicing prediction software (Splice AI, Jaganathan K, et al. 2019. PubMed ID: 30661751). This variant has been reported in multiple individuals with autosomal recessive myotonia congenita (Horga et al. 2013. PubMed ID: 23516313; Meyer et al. 2020. PubMed ID: 32670189; Vereb et al. 2020. PubMed ID: 33263785; Suetterlin et al. 2022. PubMed ID: 34529042; Vivekanandam et al. 2023. PubMed ID: 36796140; Lorenz et al. 1994. PubMed ID: 7951242; Fialho et al. 2007. PubMed ID: 17932099; Sun et al. 2001. PubMed ID: 11840191; Morrow et al. 2013. PubMed ID: 23810313). This variant is reported in 0.0031% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.