ClinVar Genomic variation as it relates to human health
NM_020435.4(GJC2):c.1234C>T (p.His412Tyr)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_020435.4(GJC2):c.1234C>T (p.His412Tyr)
Variation ID: 445910 Accession: VCV000445910.24
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q42.13 1: 228158992 (GRCh38) [ NCBI UCSC ] 1: 228346693 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Nov 5, 2017 May 1, 2024 Jan 22, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_020435.4:c.1234C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_065168.2:p.His412Tyr missense NC_000001.11:g.228158992C>T NC_000001.10:g.228346693C>T NG_011838.1:g.14141C>T - Protein change
- H412Y
- Other names
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- Canonical SPDI
- NC_000001.11:228158991:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00075
The Genome Aggregation Database (gnomAD) 0.00096
Trans-Omics for Precision Medicine (TOPMed) 0.00097
Exome Aggregation Consortium (ExAC) 0.00133
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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GJC2 | - | - |
GRCh38 GRCh37 |
325 | 368 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Uncertain significance (6) |
criteria provided, multiple submitters, no conflicts
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Mar 23, 2023 | RCV000513690.19 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 22, 2024 | RCV000633030.15 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000763840.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 1, 2018 | RCV001848882.10 | |
Uncertain significance (1) |
criteria provided, single submitter
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Sep 29, 2022 | RCV002528231.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jul 19, 2023 | RCV003323580.8 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain significance
(May 11, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000610734.1
First in ClinVar: Nov 05, 2017 Last updated: Nov 05, 2017 |
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Uncertain significance
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hypomyelinating leukodystrophy 2
Hereditary spastic paraplegia 44 Lymphatic malformation 3
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000894762.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Uncertain significance
(Mar 01, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hereditary spastic paraplegia
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, The Hospital for Sick Children
Accession: SCV002104734.1
First in ClinVar: Mar 19, 2022 Last updated: Mar 19, 2022 |
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Uncertain significance
(Apr 15, 2019)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001985354.2
First in ClinVar: Nov 05, 2021 Last updated: Mar 04, 2023 |
Comment:
Identified in individual with segmental dystonia, spasticity, and hypomyelination who also harbored 2 additional GJC2 variants (Zittel et al., 2012); Published functional studies demonstrate impaired … (more)
Identified in individual with segmental dystonia, spasticity, and hypomyelination who also harbored 2 additional GJC2 variants (Zittel et al., 2012); Published functional studies demonstrate impaired transfer of Lucifer yellow dye in cells transfected with H412Y (described as H409Y), supporting altered gap junction function (Finegold et al., 2012); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22351697, 29906362, 22833003) (less)
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Uncertain significance
(Jul 19, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004029607.1
First in ClinVar: Aug 26, 2023 Last updated: Aug 26, 2023 |
Comment:
Variant summary: GJC2 c.1234C>T (p.His412Tyr) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign … (more)
Variant summary: GJC2 c.1234C>T (p.His412Tyr) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00075 in 225966 control chromosomes (genomAD). c.1234C>T has been reported in the literature in individuals affected with lymphedema or PelizaeusMerzbacher-like disease (Finegold_2012, Zittel_2012, Michelini_2016). These reports do not provide unequivocal conclusions about association of the variant with Hypomyelinating Leukodystrophy 2. At least one functional study reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Finegold_2012). Seven ClinVar submitters (evaluation after 2014) cite this variant as uncertain significance. The following publications have been ascertained in the context of this evaluation (PMID: 22351697, 29906362, 35807022, 22833003). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Aug 05, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001713137.2
First in ClinVar: Jun 15, 2021 Last updated: May 27, 2023 |
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Uncertain significance
(Jan 22, 2024)
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criteria provided, single submitter
Method: clinical testing
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Spastic paraplegia
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000754242.8
First in ClinVar: May 28, 2018 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 412 of the GJC2 protein (p.His412Tyr). … (more)
This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 412 of the GJC2 protein (p.His412Tyr). This variant is present in population databases (rs200334298, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with lymphedema and/or Pelizaeus-Merzbacher-like disease (PMID: 22351697, 22833003, 29906362). This variant is also known as H409Y. ClinVar contains an entry for this variant (Variation ID: 445910). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GJC2 protein function. Experimental studies have shown that this missense change affects GJC2 function (PMID: 22351697). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Mar 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV004563927.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
The GJC2 c.1234C>T; p.His412Tyr variant (rs200334298), also known as H409Y, is reported in the literature in individuals affected with vascular and lymphatic malformations (Finegold 2012, … (more)
The GJC2 c.1234C>T; p.His412Tyr variant (rs200334298), also known as H409Y, is reported in the literature in individuals affected with vascular and lymphatic malformations (Finegold 2012, Michelini 2016, Serio 2022). Additionally, this variant has been reported in an individual with Pelizaeus-Merzbacher-like disease, a form of hypomyelinating leukodystrophy (Zittel 2012). This variant is found in the non-Finnish European population with an allele frequency of 0.1402% (161/114,842 alleles) in the Genome Aggregation Database. Functional analyses of the variant protein show impaired function (Finegold 2012). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.5). While this variant is unlikely to be causative of autosomal dominant lymphatic malformations, due to limited and conflicting information, its clinical significance in recessive disease is uncertain at this time. References: Finegold DN et al. Connexin 47 mutations increase risk for secondary lymphedema following breast cancer treatment. Clin Cancer Res. 2012 Apr 15;18(8):2382-90. PMID: 22351697. Michelini S et al. Genetic Screening in a Large Cohort of Italian Patients Affected by Primary Lymphedema Using a Next Generation Sequencing (NGS) Approach. Lymphology. 2016 Jun;49(2):57-72. PMID: 29906362. Serio VB et al. Nosological and Theranostic Approach to Vascular Malformation through cfDNA NGS Liquid Biopsy. J Clin Med. 2022 Jun 28;11(13):3740. PMID: 35807022. Zittel S et al. "Pelizaeus-Merzbacher-like disease" presenting as complicated hereditary spastic paraplegia. J Neurol. 2012 Nov;259(11):2498-500. PMID: 22833003. (less)
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Uncertain significance
(Sep 29, 2022)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV003709108.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
The c.1234C>T (p.H412Y) alteration is located in exon 2 (coding exon 1) of the GJC2 gene. This alteration results from a C to T substitution … (more)
The c.1234C>T (p.H412Y) alteration is located in exon 2 (coding exon 1) of the GJC2 gene. This alteration results from a C to T substitution at nucleotide position 1234, causing the histidine (H) at amino acid position 412 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001927956.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001969791.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Nosological and Theranostic Approach to Vascular Malformation through cfDNA NGS Liquid Biopsy. | Serio VB | Journal of clinical medicine | 2022 | PMID: 35807022 |
Genetic Screening in a Large Cohort of Italian Patients Affected by Primary Lymphedema Using a Next Generation Sequencing (NGS) Approach. | Michelini S | Lymphology | 2016 | PMID: 29906362 |
"Pelizaeus-Merzbacher-like disease" presenting as complicated hereditary spastic paraplegia. | Zittel S | Journal of neurology | 2012 | PMID: 22833003 |
Connexin 47 mutations increase risk for secondary lymphedema following breast cancer treatment. | Finegold DN | Clinical cancer research : an official journal of the American Association for Cancer Research | 2012 | PMID: 22351697 |
Text-mined citations for rs200334298 ...
HelpRecord last updated May 08, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.