ClinVar Genomic variation as it relates to human health
NM_032861.4(SERAC1):c.442C>T (p.Arg148Ter)
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_032861.4(SERAC1):c.442C>T (p.Arg148Ter)
Variation ID: 35556 Accession: VCV000035556.32
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 6q25.3 6: 158146827 (GRCh38) [ NCBI UCSC ] 6: 158567859 (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 9, 2017 Apr 6, 2024 Mar 14, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_032861.4:c.442C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_116250.3:p.Arg148Ter nonsense NR_073096.2:n.566C>T non-coding transcript variant NC_000006.12:g.158146827G>A NC_000006.11:g.158567859G>A NG_032889.1:g.26454C>T - Protein change
- R148*
- Other names
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- Canonical SPDI
- NC_000006.12:158146826:G:A
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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.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
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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SERAC1 | - | - |
GRCh38 GRCh37 |
397 | 429 |
Conditions - Germline
Condition
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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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Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
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Mar 14, 2024 | RCV000029218.18 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 23, 2020 | RCV000414395.6 |
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
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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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Pathogenic
(Nov 14, 2016)
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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: SCV000490978.2
First in ClinVar: Jan 09, 2017 Last updated: Jan 09, 2017 |
Comment:
The R148X nonsense variant has been reported previously in association with 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL) (Wortmann et al. (2012). The … (more)
The R148X nonsense variant has been reported previously in association with 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL) (Wortmann et al. (2012). The R148X variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. In summary, we interpret R148X to be pathogenic. (less)
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Pathogenic
(Dec 31, 2017)
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criteria provided, single submitter
Method: clinical testing
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3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome
Affected status: yes
Allele origin:
germline
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Baylor Genetics
Accession: SCV000992824.1
First in ClinVar: Sep 21, 2019 Last updated: Sep 21, 2019 |
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Pathogenic
(Mar 15, 2022)
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criteria provided, single submitter
Method: clinical testing
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3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV002554869.1
First in ClinVar: Jul 30, 2022 Last updated: Jul 30, 2022 |
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Pathogenic
(May 10, 2019)
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criteria provided, single submitter
Method: clinical testing
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3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome
Affected status: yes
Allele origin:
inherited
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Center for Molecular Medicine, Children’s Hospital of Fudan University
Accession: SCV001190548.1
First in ClinVar: Mar 29, 2020 Last updated: Mar 29, 2020 |
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Pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001447083.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Hyperammonemia (present) , Hypokalemia (present) , Lactic acidosis (present) , 3-Methylglutaconic aciduria (present)
Sex: male
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Pathogenic
(Mar 14, 2024)
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criteria provided, single submitter
Method: research
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3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004801248.2
First in ClinVar: Mar 16, 2024 Last updated: Apr 06, 2024 |
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Likely pathogenic
(Sep 26, 2019)
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no assertion criteria provided
Method: clinical testing
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3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome
Affected status: yes
Allele origin:
germline
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Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City
Accession: SCV001133068.1
First in ClinVar: Jan 06, 2020 Last updated: Jan 06, 2020 |
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Pathogenic
(Jun 10, 2012)
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no assertion criteria provided
Method: literature only
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3-@METHYLGLUTACONIC ACIDURIA WITH DEAFNESS, ENCEPHALOPATHY, AND LEIGH-LIKE SYNDROME
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000051864.3
First in ClinVar: Apr 04, 2013 Last updated: Nov 20, 2021 |
Comment on evidence:
In 3 members of a consanguineous Turkish family with 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL; 614739), Wortmann et al. (2012) identified a … (more)
In 3 members of a consanguineous Turkish family with 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL; 614739), Wortmann et al. (2012) identified a homozygous 442C-T transition in the SERAC1 gene, resulting in an arg148-to-ter (R148X) substitution. The mutation was identified by exome sequencing and confirmed by Sanger sequencing, and was not found in 369 controls. The index patient had previously been reported as patient 3 by Wortmann et al. (2006). Clinical features included psychomotor retardation, recurrent infections in infancy, hypoglycemia, spasticity, dystonia, sensorineural deafness, brain atrophy, and lesions on brain imaging. Laboratory studies showed increased serum lactate and alanine, urinary 3-MGA, mitochondrial oxidative phosphorylation defects, abnormal mitochondria, an abnormal phosphatidylglycerol and cardiolipin spectrum in fibroblasts, and abnormal accumulation of unesterified cholesterol within cells. In a Saudi Arabian patient with MEGDEL, Lumish et al. (2014) identified compound heterozygous mutations in the SERAC1 gene: R148X and a 1-bp deletion (c.438delC; 614725.0010) in the SERAC1 gene, predicted to result in a frameshift and premature termination (Thr147fsTer22). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. The patient's father was shown to be a carrier of the c.438delC mutation. The c.438delC mutation was not present in the 1000 Genomes Project and EVS databases. (less)
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Pathogenic
(Apr 01, 2023)
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no assertion criteria provided
Method: clinical testing
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3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome
Affected status: yes
Allele origin:
germline
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Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)
Accession: SCV003927950.1
First in ClinVar: Sep 16, 2023 Last updated: Sep 16, 2023 |
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome
Affected status: yes
Allele origin:
germline
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Pathology and Clinical Laboratory Medicine, King Fahad Medical City
Accession: SCV001438878.1
First in ClinVar: Oct 25, 2020 Last updated: Oct 25, 2020 |
Ethnicity/Population group: Arab
Geographic origin: Middle East
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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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[MEGDEL syndrome with an SERAC1 mutation: a case report]. | Chen J | Zhonghua er ke za zhi = Chinese journal of pediatrics | 2017 | PMID: 28482397 |
The Expanding MEGDEL Phenotype: Optic Nerve Atrophy, Microcephaly, and Myoclonic Epilepsy in a Child with SERAC1 Mutations. | Lumish HS | JIMD reports | 2014 | PMID: 24997715 |
Mutations in the phospholipid remodeling gene SERAC1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness. | Wortmann SB | Nature genetics | 2012 | PMID: 22683713 |
Association of 3-methylglutaconic aciduria with sensori-neural deafness, encephalopathy, and Leigh-like syndrome (MEGDEL association) in four patients with a disorder of the oxidative phosphorylation. | Wortmann S | Molecular genetics and metabolism | 2006 | PMID: 16527507 |
Text-mined citations for rs387907236 ...
HelpRecord last updated Apr 06, 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.