This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 11 of the C19orf12 protein (p.Thr11Met). This variant is present in population databases (rs397514477, gnomAD 0.004%). This missense change has been observed in individuals with autosomal recessive neurodegeneration with brain iron accumulation (PMID: 21981780, 23278385, 23436634, 25592411). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 31156). 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 tolerated. For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_031448.6(C19orf12):c.-2C>T
Germline
Classification
Help
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.
(11)
Help
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.
Pathogenic/Likely pathogenic
11
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_031448.6(C19orf12):c.-2C>T
Variation ID: 31156 Accession: VCV000031156.39
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 19q12 19: 29708415 (GRCh38) [ NCBI UCSC ] 19: 30199322 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Mar 24, 2015 Oct 20, 2024 Jul 15, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_031448.6:c.-2C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
5 prime UTR NM_001031726.4:c.-2C>T 5 prime UTR NM_001256046.3:c.-2C>T 5 prime UTR NM_001256047.2:c.-2C>T 5 prime UTR NM_001282929.1:c.-32-5438C>T intron variant NM_001282930.3:c.-32-5438C>T intron variant NM_001282931.3:c.-315C>T 5 prime UTR NR_045692.1:n.430C>T NC_000019.10:g.29708415G>A NC_000019.9:g.30199322G>A NG_031970.2:g.12375C>T Q9NSK7:p.Thr11Met - Protein change
- T11M
- Other names
-
C19ORF12, THR11MET
NM_001031726.3(C19orf12):c.32C>T(p.Thr11Met)
- Canonical SPDI
- NC_000019.10:29708414:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD) 0.00003
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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. |
|||
| C19orf12 | - | - |
GRCh38 GRCh37 |
283 | 324 | |
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Nov 24, 2020 | RCV000024152.24 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jun 1, 2017 | RCV000426086.28 | |
| Pathogenic (1) |
no assertion criteria provided
|
- | RCV001004003.9 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 1, 2023 | RCV003743545.3 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jul 15, 2024 | RCV004700277.1 |
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
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
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Dec 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary spastic paraplegia 43
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004550935.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 11 of the C19orf12 protein (p.Thr11Met). … (more)
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 11 of the C19orf12 protein (p.Thr11Met). This variant is present in population databases (rs397514477, gnomAD 0.004%). This missense change has been observed in individuals with autosomal recessive neurodegeneration with brain iron accumulation (PMID: 21981780, 23278385, 23436634, 25592411). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 31156). 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 tolerated. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Likely Pathogenic
(Nov 24, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Neurodegeneration with brain iron accumulation 4
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004848517.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Thr11Met variant in C19orf12 has been identified in at least 13 individuals (9 consanguinous homozygous individuals and 2 compound heterozygous individuals) with neurodegeneration with … (more)
The p.Thr11Met variant in C19orf12 has been identified in at least 13 individuals (9 consanguinous homozygous individuals and 2 compound heterozygous individuals) with neurodegeneration with brain iron accumulation (NBIA) and segregated with disease in at least 5 affected members of 4 families (Hartig 2001 PMID 21981780, Schulte 2013 PMID 23436634, Gore 2016 PMID 27801611, Olgiati 2017 PMID 28347615, Alavi 2020 PMID 31970231). It has also been reported as Pathogenic by multiple laboratories in ClinVar (Variation ID 31156) and was identified in 0.004% (1/24194) African chromosomes and 0.001% (1/128668) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org/). This variant falls in noncoding regions of the most abundantly expressed C19orf12 transcripts and functional studies assessing its impact are not available. Additionally, computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive NBIA. ACMG/AMP Criteria applied: PP1_Strong, PM3, PM2_Supporting, BP4. (less)
|
|
|
Pathogenic
(Apr 30, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000516753.3
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
Comment:
The T11M variant in the C19orf12 gene has been reported in the homozygous or compound heterozygousstate in multiple individuals with neurodegeneration with brain iron accumulation … (more)
The T11M variant in the C19orf12 gene has been reported in the homozygous or compound heterozygousstate in multiple individuals with neurodegeneration with brain iron accumulation (Hartig et al., 2011;Schulte et al., 2013). Several individuals with a homozygous T11M variant exhibited early adulthood onsetof dystonia, spasticity, progressive dementia, and psychiatric disorders, including one individual with aParkinson-like phenotype (Tschentscher et al., 2015). The T11M substitution was not observed inapproximately 6100 individuals of European and African American ancestry in the NHLBI ExomeSequencing Project, indicating it is not a common benign variant in these populations. The T11M variant isa non-conservative amino acid substitution, which is likely to impact secondary protein structure as theseresidues differ in polarity, charge, size and/or other properties. Another missense variant in a nearbyresidue (D18G) has also been reported in the Human Gene Mutation Database in association withneurodegeneration with brain iron accumulation (Stenson et al., 2014), supporting the functional importanceof this region of the protein. We interpret T11M as a pathogenic variant. (less)
|
|
|
Pathogenic
(May 31, 2018)
|
criteria provided, single submitter
Method: curation
|
Neurodegeneration with brain iron accumulation 4
Affected status: unknown
Allele origin:
unknown
|
SIB Swiss Institute of Bioinformatics
Accession: SCV000803518.1
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Comment:
This variant is interpreted as a Pathogenic, for Neurodegeneration with brain iron accumulation 4, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM2 … (more)
This variant is interpreted as a Pathogenic, for Neurodegeneration with brain iron accumulation 4, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => Recurrent mutation observed in multiple unrelated patients (PMID:22584950,23278385,21981780,25592411,23166001,23436634). PM3 => For recessive disorders, detected in trans with a pathogenic variant (PMID:21981780,23436634). PP1-Strong => PP1 upgraded in strength to Strong (PMID:23278385,28347615). (less)
|
|
|
Pathogenic
(Apr 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Neurodegeneration with brain iron accumulation 4
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000411389.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
The C19orf12 c.32C>T (p.Thr11Met) variant, which has been described as one of the most common variants associated with mitochondrial membrane protein-associated neurodegeneration, has been identified … (more)
The C19orf12 c.32C>T (p.Thr11Met) variant, which has been described as one of the most common variants associated with mitochondrial membrane protein-associated neurodegeneration, has been identified in a homozygous state in nine individuals and in a compound heterozygous state in three individuals (Hartig et al. 2011; Deschauer et al. 2012; Dezfouli et al. 2012; Dogu et al. 2013; Tschentscher et al. 2015). The variant was absent from 750 control chromosomes (Hartig et al. 2011) and has not been reported in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium. It has been suggested that the variant may be associated with a later age of onset since it affects only the longer isoform of the protein (Tschentscher et al. 2015). Based on the evidence, the variant is classified as pathogenic for mitochondrial membrane protein-associated neurodegeneration. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
|
|
|
Likely pathogenic
(Mar 31, 2020)
|
criteria provided, single submitter
Method: research
|
Neurodegeneration with brain iron accumulation 4
Affected status: yes
Allele origin:
germline
|
Suna and Inan Kirac Foundation Neurodegeneration Research Laboratory, Koc University
Accession: SCV001251026.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Number of individuals with the variant: 1
Geographic origin: Anatolian Peninsula
|
|
|
Pathogenic
(Jul 15, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Neurodegeneration with brain iron accumulation
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV005203602.1
First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024 |
Comment:
Variant summary: C19orf12 c.-2C>T (commonly known as c.32C>T, p.Thr11Met in the literature) is located in the untranslated mRNA region upstream of the initiation codon. The … (more)
Variant summary: C19orf12 c.-2C>T (commonly known as c.32C>T, p.Thr11Met in the literature) is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 8e-06 in 249206 control chromosomes (gnomAD). c.-2C>T has been reported in the literature in multiple individuals including homozygous individuals of Turkish origin, affected with neurodegeneration with brain iron accumulation (examples: Tschentscher_2015, Sparber_2021, Dogu_2013). In several families the variant segregated with the disease. These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 25592411, 33607528, 23278385). ClinVar contains an entry for this variant (Variation ID: 31156). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Jun 01, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001246909.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Oct 01, 2013)
|
no assertion criteria provided
Method: literature only
|
NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 4, AUTOSOMAL RECESSIVE
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000045443.6
First in ClinVar: Apr 04, 2013 Last updated: Nov 23, 2019 |
Comment on evidence:
In a Polish patient with neurodegeneration with brain iron accumulation-4 (NBIA4; 614298), Hartig et al. (2011) identified a homozygous c.32C-T transition (c.32C-T, NM_001031726.2) in the … (more)
In a Polish patient with neurodegeneration with brain iron accumulation-4 (NBIA4; 614298), Hartig et al. (2011) identified a homozygous c.32C-T transition (c.32C-T, NM_001031726.2) in the C19ORF12 gene, resulting in a thr11-to-met (T11M) substitution upstream of the initiation codon of the shorter isoform, thus only affecting the longer isoform. Another patient was compound heterozygous for T11M and the founder 11-bp deletion (614297.0001). Neither mutation was found in 750 control chromosomes. Dogu et al. (2013) identified a homozygous T11M mutation in 3 affected individuals from 2 unrelated consanguineous Turkish families with NBIA4. The mutation was found by homozygosity mapping and candidate gene sequencing. All patients had a relatively late onset of the disorder, between 25 and 29 years of age, and 2 showed very rapid progression leading to death 12 and 36 months after admission, respectively. The features were typical of the disorder, with progressive parkinsonism unresponsive to L-DOPA therapy, pyramidal signs, and tremor. Two of the 3 patients had cognitive impairment with behavioral abnormalities. Dogu et al. (2013) suggested that the phenotypic variation in these patients compared to previously reported NBIA4 patients may be due to the involvement of other genetic, epigenetic, or environmental factors. (less)
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Pathogenic
(-)
|
no assertion criteria provided
Method: research
|
Abnormality of iron homeostasis
Affected status: yes
Allele origin:
unknown
|
NIHR Bioresource Rare Diseases, University of Cambridge
Accession: SCV001162047.1
First in ClinVar: Feb 27, 2020 Last updated: Feb 27, 2020 |
Number of individuals with the variant: 1
Sex: female
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Neurodegeneration with brain iron accumulation 4
Affected status: unknown
Allele origin:
germline
|
GeneReviews
Accession: SCV000153730.4
First in ClinVar: May 30, 2014 Last updated: Oct 01, 2022 |
Comment:
Founder variant in Turkish population (Olgiati et al 2017); Mean age of onset is 25 yrs in persons homozygous for this variant (Hartig et al … (more)
Founder variant in Turkish population (Olgiati et al 2017); Mean age of onset is 25 yrs in persons homozygous for this variant (Hartig et al 2013). (less)
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Comment:
Comment:
The p.Thr11Met variant in C19orf12 has been identified in at least 13 individuals (9 consanguinous homozygous individuals and 2 compound heterozygous individuals) with neurodegeneration with brain iron accumulation (NBIA) and segregated with disease in at least 5 affected members of 4 families (Hartig 2001 PMID 21981780, Schulte 2013 PMID 23436634, Gore 2016 PMID 27801611, Olgiati 2017 PMID 28347615, Alavi 2020 PMID 31970231). It has also been reported as Pathogenic by multiple laboratories in ClinVar (Variation ID 31156) and was identified in 0.004% (1/24194) African chromosomes and 0.001% (1/128668) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org/). This variant falls in noncoding regions of the most abundantly expressed C19orf12 transcripts and functional studies assessing its impact are not available. Additionally, computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive NBIA. ACMG/AMP Criteria applied: PP1_Strong, PM3, PM2_Supporting, BP4.
Comment:
The T11M variant in the C19orf12 gene has been reported in the homozygous or compound heterozygousstate in multiple individuals with neurodegeneration with brain iron accumulation (Hartig et al., 2011;Schulte et al., 2013). Several individuals with a homozygous T11M variant exhibited early adulthood onsetof dystonia, spasticity, progressive dementia, and psychiatric disorders, including one individual with aParkinson-like phenotype (Tschentscher et al., 2015). The T11M substitution was not observed inapproximately 6100 individuals of European and African American ancestry in the NHLBI ExomeSequencing Project, indicating it is not a common benign variant in these populations. The T11M variant isa non-conservative amino acid substitution, which is likely to impact secondary protein structure as theseresidues differ in polarity, charge, size and/or other properties. Another missense variant in a nearbyresidue (D18G) has also been reported in the Human Gene Mutation Database in association withneurodegeneration with brain iron accumulation (Stenson et al., 2014), supporting the functional importanceof this region of the protein. We interpret T11M as a pathogenic variant.
Comment:
This variant is interpreted as a Pathogenic, for Neurodegeneration with brain iron accumulation 4, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => Recurrent mutation observed in multiple unrelated patients (PMID:22584950,23278385,21981780,25592411,23166001,23436634). PM3 => For recessive disorders, detected in trans with a pathogenic variant (PMID:21981780,23436634). PP1-Strong => PP1 upgraded in strength to Strong (PMID:23278385,28347615).
Comment:
The C19orf12 c.32C>T (p.Thr11Met) variant, which has been described as one of the most common variants associated with mitochondrial membrane protein-associated neurodegeneration, has been identified in a homozygous state in nine individuals and in a compound heterozygous state in three individuals (Hartig et al. 2011; Deschauer et al. 2012; Dezfouli et al. 2012; Dogu et al. 2013; Tschentscher et al. 2015). The variant was absent from 750 control chromosomes (Hartig et al. 2011) and has not been reported in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium. It has been suggested that the variant may be associated with a later age of onset since it affects only the longer isoform of the protein (Tschentscher et al. 2015). Based on the evidence, the variant is classified as pathogenic for mitochondrial membrane protein-associated neurodegeneration. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Comment:
Variant summary: C19orf12 c.-2C>T (commonly known as c.32C>T, p.Thr11Met in the literature) is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 8e-06 in 249206 control chromosomes (gnomAD). c.-2C>T has been reported in the literature in multiple individuals including homozygous individuals of Turkish origin, affected with neurodegeneration with brain iron accumulation (examples: Tschentscher_2015, Sparber_2021, Dogu_2013). In several families the variant segregated with the disease. These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 25592411, 33607528, 23278385). ClinVar contains an entry for this variant (Variation ID: 31156). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Founder variant in Turkish population (Olgiati et al 2017); Mean age of onset is 25 yrs in persons homozygous for this variant (Hartig et al 2013).
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. |
Comment:
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 11 of the C19orf12 protein (p.Thr11Met). This variant is present in population databases (rs397514477, gnomAD 0.004%). This missense change has been observed in individuals with autosomal recessive neurodegeneration with brain iron accumulation (PMID: 21981780, 23278385, 23436634, 25592411). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 31156). 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 tolerated. For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.Thr11Met variant in C19orf12 has been identified in at least 13 individuals (9 consanguinous homozygous individuals and 2 compound heterozygous individuals) with neurodegeneration with brain iron accumulation (NBIA) and segregated with disease in at least 5 affected members of 4 families (Hartig 2001 PMID 21981780, Schulte 2013 PMID 23436634, Gore 2016 PMID 27801611, Olgiati 2017 PMID 28347615, Alavi 2020 PMID 31970231). It has also been reported as Pathogenic by multiple laboratories in ClinVar (Variation ID 31156) and was identified in 0.004% (1/24194) African chromosomes and 0.001% (1/128668) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org/). This variant falls in noncoding regions of the most abundantly expressed C19orf12 transcripts and functional studies assessing its impact are not available. Additionally, computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive NBIA. ACMG/AMP Criteria applied: PP1_Strong, PM3, PM2_Supporting, BP4.
Comment:
The T11M variant in the C19orf12 gene has been reported in the homozygous or compound heterozygousstate in multiple individuals with neurodegeneration with brain iron accumulation (Hartig et al., 2011;Schulte et al., 2013). Several individuals with a homozygous T11M variant exhibited early adulthood onsetof dystonia, spasticity, progressive dementia, and psychiatric disorders, including one individual with aParkinson-like phenotype (Tschentscher et al., 2015). The T11M substitution was not observed inapproximately 6100 individuals of European and African American ancestry in the NHLBI ExomeSequencing Project, indicating it is not a common benign variant in these populations. The T11M variant isa non-conservative amino acid substitution, which is likely to impact secondary protein structure as theseresidues differ in polarity, charge, size and/or other properties. Another missense variant in a nearbyresidue (D18G) has also been reported in the Human Gene Mutation Database in association withneurodegeneration with brain iron accumulation (Stenson et al., 2014), supporting the functional importanceof this region of the protein. We interpret T11M as a pathogenic variant.
Comment:
This variant is interpreted as a Pathogenic, for Neurodegeneration with brain iron accumulation 4, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => Recurrent mutation observed in multiple unrelated patients (PMID:22584950,23278385,21981780,25592411,23166001,23436634). PM3 => For recessive disorders, detected in trans with a pathogenic variant (PMID:21981780,23436634). PP1-Strong => PP1 upgraded in strength to Strong (PMID:23278385,28347615).
Comment:
The C19orf12 c.32C>T (p.Thr11Met) variant, which has been described as one of the most common variants associated with mitochondrial membrane protein-associated neurodegeneration, has been identified in a homozygous state in nine individuals and in a compound heterozygous state in three individuals (Hartig et al. 2011; Deschauer et al. 2012; Dezfouli et al. 2012; Dogu et al. 2013; Tschentscher et al. 2015). The variant was absent from 750 control chromosomes (Hartig et al. 2011) and has not been reported in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium. It has been suggested that the variant may be associated with a later age of onset since it affects only the longer isoform of the protein (Tschentscher et al. 2015). Based on the evidence, the variant is classified as pathogenic for mitochondrial membrane protein-associated neurodegeneration. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Comment:
Variant summary: C19orf12 c.-2C>T (commonly known as c.32C>T, p.Thr11Met in the literature) is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 8e-06 in 249206 control chromosomes (gnomAD). c.-2C>T has been reported in the literature in multiple individuals including homozygous individuals of Turkish origin, affected with neurodegeneration with brain iron accumulation (examples: Tschentscher_2015, Sparber_2021, Dogu_2013). In several families the variant segregated with the disease. These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 25592411, 33607528, 23278385). ClinVar contains an entry for this variant (Variation ID: 31156). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Founder variant in Turkish population (Olgiati et al 2017); Mean age of onset is 25 yrs in persons homozygous for this variant (Hartig et al 2013).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Retrospective analysis of 17 patients with mitochondrial membrane protein-associated neurodegeneration diagnosed in Russia. | Sparber P | Parkinsonism & related disorders | 2021 | PMID: 33607528 |
| Mitochondrial Membrane Protein-Associated Neurodegeneration. | Adam MP | - | 2021 | PMID: 24575447 |
| Whole-genome sequencing of patients with rare diseases in a national health system. | Turro E | Nature | 2020 | PMID: 32581362 |
| Late-Onset Mitochondrial Membrane Protein-Associated Neurodegeneration With Extensive Brain Iron Deposition. | Alavi A | Movement disorders clinical practice | 2019 | PMID: 31970231 |
| The p.Thr11Met mutation in c19orf12 is frequent among adult Turkish patients with MPAN. | Olgiati S | Parkinsonism & related disorders | 2017 | PMID: 28347615 |
| Clinical and imaging characteristics of late onset mitochondrial membrane protein-associated neurodegeneration (MPAN). | Gore E | Neurocase | 2016 | PMID: 27801611 |
| Analysis of the C19orf12 and WDR45 genes in patients with neurodegeneration with brain iron accumulation. | Tschentscher A | Journal of the neurological sciences | 2015 | PMID: 25592411 |
| Mitochondrial membrane protein-associated neurodegeneration (MPAN). | Hartig M | International review of neurobiology | 2013 | PMID: 24209434 |
| Mitochondrial membrane protein associated neurodegenration: a novel variant of neurodegeneration with brain iron accumulation. | Schulte EC | Movement disorders : official journal of the Movement Disorder Society | 2013 | PMID: 23436634 |
| Rapid disease progression in adult-onset mitochondrial membrane protein-associated neurodegeneration. | Dogu O | Clinical genetics | 2013 | PMID: 23278385 |
| PANK2 and C19orf12 mutations are common causes of neurodegeneration with brain iron accumulation. | Dezfouli MA | Movement disorders : official journal of the Movement Disorder Society | 2013 | PMID: 23166001 |
| C19orf12 mutations in neurodegeneration with brain iron accumulation mimicking juvenile amyotrophic lateral sclerosis. | Deschauer M | Journal of neurology | 2012 | PMID: 22584950 |
| Absence of an orphan mitochondrial protein, c19orf12, causes a distinct clinical subtype of neurodegeneration with brain iron accumulation. | Hartig MB | American journal of human genetics | 2011 | PMID: 21981780 |
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Text-mined citations for rs397514477 ...
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Record last updated Nov 30, 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.