NM_000083.3(CLCN1):c.568_569delinsTC (p.Gly190Ser) AND not provided

Clinical significance:Conflicting interpretations of pathogenicity, Pathogenic(2);Uncertain significance(1) (Last evaluated: Apr 23, 2021)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000489144.4

Allele description [Variation Report for NM_000083.3(CLCN1):c.568_569delinsTC (p.Gly190Ser)]

NM_000083.3(CLCN1):c.568_569delinsTC (p.Gly190Ser)

Gene:
CLCN1:chloride voltage-gated channel 1 [Gene - OMIM - HGNC]
Variant type:
Indel
Cytogenetic location:
7q34
Genomic location:
Preferred name:
NM_000083.3(CLCN1):c.568_569delinsTC (p.Gly190Ser)
HGVS:
  • NC_000007.14:g.143321720_143321721delinsTC
  • NG_009815.1:g.10595_10596delinsTC
  • NG_009815.2:g.10595_10596delinsTC
  • NM_000083.3:c.568_569delinsTCMANE SELECT
  • NP_000074.3:p.Gly190Ser
  • NC_000007.13:g.143018813_143018814delinsTC
  • NM_000083.2:c.568_569delGGinsTC
  • NR_046453.2:n.670_671delinsTC
  • p.GLY190SER
Protein change:
G190S
Links:
dbSNP: rs797045032
NCBI 1000 Genomes Browser:
rs797045032
Molecular consequence:
  • NM_000083.3:c.568_569delinsTC - missense variant - [Sequence Ontology: SO:0001583]
  • NR_046453.2:n.670_671delinsTC - non-coding transcript variant - [Sequence Ontology: SO:0001619]
Observations:
1

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000577243GeneDxcriteria provided, single submitter
Pathogenic
(Mar 13, 2018)
germlineclinical testing

Citation Link,

SCV000612791Athena Diagnostics Inccriteria provided, single submitter
Pathogenic
(Apr 23, 2021)
unknownclinical testing

PubMed (15)
[See all records that cite these PMIDs]

SCV000704674EGL Genetic Diagnostics, Eurofins Clinical Diagnosticscriteria provided, single submitter
Uncertain significance
(Jan 13, 2017)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknown1not providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Functional characterization of ClC-1 mutations from patients affected by recessive myotonia congenita presenting with different clinical phenotypes.

Desaphy JF, Gramegna G, Altamura C, Dinardo MM, Imbrici P, George AL Jr, Modoni A, Lomonaco M, Conte Camerino D.

Exp Neurol. 2013 Oct;248:530-40. doi: 10.1016/j.expneurol.2013.07.018. Epub 2013 Aug 8.

PubMed [citation]
PMID:
23933576
PMCID:
PMC3781327

Congenital myotonia: a review of twenty cases and a new splice-site mutation in the CLCN1 gene.

Özgün N, Taşlıdere H.

Turk J Pediatr. 2020;62(3):450-460. doi: 10.24953/turkjped.2020.03.012. Review.

PubMed [citation]
PMID:
32558419
See all PubMed Citations (15)

Details of each submission

From GeneDx, SCV000577243.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The c.568_569delGGinsTC variant in the CLCN1 gene has been previously reported in thehomozygous, compound heterozygous, and heterozygous states in association with myotoniacongenita (Shalata et al., 2010; Ulzi et al., 2012). Homozygotes and compound heterozygotes were moderately to severely affected with disease onset in the first decade of life. Heterozygotes were asymptomatic or mildly affected and only had limb contraction involvement (Shalata et al., 2010). The c.568_569delGGinsTC variant causes an in-frame replacement, changing a Glycine residue at codon 190 to a Serine residue, denoted p.Gly190Ser. The c.568_569delGGinsTC variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. Functional studies revealed that patch clamp analysis of the c.568_569delGGinsTC variant in HEK293 cells showed dramatic positive shift of activation voltage-dependence resulting in almost no detectable chloride currents (Desaphy et al., 2013). The c.568_569delGGinsTC variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.568_569delGGinsTC as a pathogenic variant.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Athena Diagnostics Inc, SCV000612791.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (15)

Description

This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls and therefore is consistent with pathogenicity (http://gnomad.broadinstitute.org). At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. This variant segregates with disease in at least one family. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant was shown to impair channel function by reducing permeability, current density and affecting channel deactivation properties (PMID: 22521272, 23933576). 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From EGL Genetic Diagnostics, Eurofins Clinical Diagnostics, SCV000704674.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided1not providednot providednot provided

Last Updated: Sep 18, 2021

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