ClinVar Genomic variation as it relates to human health
NM_001031726.4(C19orf12):c.164_166delGGG
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_001031726.4(C19orf12):c.164_166delGGG
Variation ID: 88866 Accession: VCV000088866.28
- Type and length
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Deletion, 3 bp
- Location
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Cytogenetic: 19q12 19: 29702972-29702974 (GRCh38) [ NCBI UCSC ] 19: 30193879-30193881 (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 Jan 13, 2019 Apr 15, 2024 Mar 29, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001031726.3:c.197_199delGGG NM_001031726.4:c.164_166delGGG splice acceptor NC_000019.10:g.29702976_29702978del NC_000019.9:g.30193883_30193885del NG_031970.2:g.17816_17818del - Protein change
- Other names
- C19ORF12, 3-BP DEL, NT197
- Canonical SPDI
- NC_000019.10:29702971:CCCCCCC:CCCC
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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.
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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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C19orf12 | - | - |
GRCh38 GRCh37 |
277 | 318 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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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Pathogenic (2) |
criteria provided, single submitter
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Nov 8, 2022 | RCV000074455.18 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jan 27, 2022 | RCV001311507.27 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Mar 29, 2023 | RCV002265593.9 |
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
Help
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
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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
Help
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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Likely pathogenic
(Mar 29, 2023)
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criteria provided, single submitter
Method: clinical testing
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Neurodegeneration with brain iron accumulation
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002548112.2
First in ClinVar: Jul 18, 2022 Last updated: Jun 03, 2023 |
Comment:
Variant summary: C19orf12 c.164_166delGGG/p.Gly55del (legacy name: c.197_199delGGG/p.Gly66del) results in an in-frame deletion that is predicted to remove one amino acid from the transmembrane domain of … (more)
Variant summary: C19orf12 c.164_166delGGG/p.Gly55del (legacy name: c.197_199delGGG/p.Gly66del) results in an in-frame deletion that is predicted to remove one amino acid from the transmembrane domain of the encoded protein. The variant allele was found at a frequency of 1.2e-05 in 248898 control chromosomes. c.164_166delGGG has been reported in the literature as a compound heterozygous genotype in at-least three individuals affected with Neurodegeneration With Brain Iron Accumulation (example, Deschauer_2012 cited in Dusek_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Pathogenic
(Nov 08, 2022)
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criteria provided, single submitter
Method: clinical testing
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Neurodegeneration with brain iron accumulation 4
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
maternal
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV004045891.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Dystonic disorder (present) , Spasticity (present) , Cerebellar ataxia (present) , Iron accumulation in brain (present)
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Pathogenic
(Sep 01, 2020)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001501702.17
First in ClinVar: Mar 14, 2021 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Jan 27, 2022)
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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: SCV002558625.2
First in ClinVar: Aug 08, 2022 Last updated: Mar 04, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In-frame deletion of 1 amino acid in a non-repeat region; Published functional studies demonstrate abnormal … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In-frame deletion of 1 amino acid in a non-repeat region; Published functional studies demonstrate abnormal subcellular protein distribution (Landoure et al., 2013); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23857908, 22584950) (less)
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Pathogenic
(Oct 01, 2013)
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no assertion criteria provided
Method: literature only
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NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 4, AUTOSOMAL RECESSIVE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000108471.5
First in ClinVar: Nov 28, 2013 Last updated: Jul 22, 2019 |
Comment on evidence:
In 2 sibs with neurodegeneration with brain iron accumulation-4 (NBIA4; 614298), Deschauer et al. (2012) identified compound heterozygous mutations in the C19ORF12 gene: a 3-bp … (more)
In 2 sibs with neurodegeneration with brain iron accumulation-4 (NBIA4; 614298), Deschauer et al. (2012) identified compound heterozygous mutations in the C19ORF12 gene: a 3-bp in-frame deletion (c.197_199del), resulting in the deletion of a highly conserved residue (Gly33) in the predicted transmembrane domain, and a T11M substitution (614297.0002). The mother was heterozygous for the T11M mutation; DNA from the father was not available. The 3-bp deletion was not found in 1,000 control chromosomes and was absent from 80 HapMap individuals and the 1000 Genomes Project database. The patients were 27 and 17 years of age at the time of the report. Both had upper and lower motor neuron signs with pes cavus, winged scapula, and calf atrophy, and some difficulty walking. One had hyporeflexia with extensor plantar responses, whereas the other had hyperreflexia with clonus. Nerve studies showed reduced amplitudes with normal conduction times, consistent with axonal neuropathy. Both patients also had cognitive impairment with disinhibited and impulsive behavior; the younger sib had a history of global developmental delay since age 3 years. A third unrelated patient with a similar disorder was found to be compound heterozygous for the 3-bp deletion and an 11-bp deletion (614297.0001). Each unaffected parent was heterozygous for 1 of the mutations. This patient had onset of gait difficulties at age 9 years, distal muscle weakness, hyperreflexia, pes cavus, atrophy of the thenar muscles, learning difficulties, visual impairment due to optic atrophy, and emotional lability. Brain MRI of all 3 patients showed T2-weighted hypointensities in the global pallidus with some hypointensities also in the substantia nigra and cerebral peduncles, consistent with iron deposition. Deschauer et al. (2012) noted that the phenotype was reminiscent of juvenile-onset amyotrophic lateral sclerosis (ALS). Landoure et al. (2013) identified a homozygous c.197_199del in a patient with NBIA4. He presented at age 4 years with speech difficulty followed by progressive spasticity and impaired walking. Other features included psychomotor slowness, weakness and atrophy of the distal extremities, and small, pale optic discs. EMG showed denervation consistent with a motor neuropathy, and brain MRI showed iron deposition in the globus pallidus. In vitro functional expression studies in COS-7 cells showed that the mutant protein had a different intracellular localization compared to wildtype, with more generalized distribution throughout the cytoplasm rather than normal localization to the mitochondria or endoplasmic reticulum. (less)
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Pathogenic
(-)
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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, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001807530.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021 |
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Pathogenic
(-)
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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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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001741932.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 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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Brain iron and metabolic abnormalities in C19orf12 mutation carriers: A 7.0 tesla MRI study in mitochondrial membrane protein-associated neurodegeneration. | Dusek P | Movement disorders : official journal of the Movement Disorder Society | 2020 | PMID: 31518459 |
Hereditary spastic paraplegia type 43 (SPG43) is caused by mutation in C19orf12. | Landouré G | Human mutation | 2013 | PMID: 23857908 |
C19orf12 mutations in neurodegeneration with brain iron accumulation mimicking juvenile amyotrophic lateral sclerosis. | Deschauer M | Journal of neurology | 2012 | PMID: 22584950 |
Text-mined citations for rs398122409 ...
HelpRecord last updated Apr 20, 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.