NM_032861.4(SERAC1):c.442C>T (p.Arg148Ter) AND 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome

Clinical significance:Pathogenic (Last evaluated: May 10, 2019)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
5 submissions [Details]
Record status:
current
Accession:
RCV000029218.8

Allele description [Variation Report for NM_032861.4(SERAC1):c.442C>T (p.Arg148Ter)]

NM_032861.4(SERAC1):c.442C>T (p.Arg148Ter)

Gene:
SERAC1:serine active site containing 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
6q25.3
Genomic location:
Preferred name:
NM_032861.4(SERAC1):c.442C>T (p.Arg148Ter)
HGVS:
  • NC_000006.12:g.158146827G>A
  • NG_032889.1:g.26454C>T
  • NM_032861.4:c.442C>TMANE SELECT
  • NP_116250.3:p.Arg148Ter
  • NC_000006.11:g.158567859G>A
  • NM_032861.3:c.442C>T
  • NR_073096.2:n.566C>T
Protein change:
R148*; ARG148TER
Links:
OMIM: 614725.0001; dbSNP: rs387907236
NCBI 1000 Genomes Browser:
rs387907236
Molecular consequence:
  • NR_073096.2:n.566C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NM_032861.4:c.442C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:
3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL)
Synonyms:
3-METHYLGLUTACONIC ACIDURIA, TYPE VI; 3-METHYLGLUTACONIC ACIDURIA WITH DYSTONIA-DEAFNESS, HEPATOPATHY, ENCEPHALOPATHY, AND LEIGH-LIKE SYNDROME; MEGDEL syndrome
Identifiers:
MONDO: MONDO:0013875; MedGen: C3553597; Orphanet: 352328; OMIM: 614739

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000051864OMIMno assertion criteria providedPathogenic
(Nov 17, 2021)
germlineliterature only

PubMed (1)
[See all records that cite this PMID]

Wortmann, S., Rodenburg, R. J. T., Huizing, M., Loupatty, F. J., de Koning, T., Kluijtmans, L. A. J., Engelke, U., Wevers, R., Smeitink, J. A. M., Morava, E. 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. Molec. Genet. Metab. 88: 47-52, 2006.,

SCV000992824Baylor Geneticscriteria provided, single submitter
Pathogenic
(Dec 31, 2017)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV001133068Biochemical Molecular Genetic Laboratory,King Abdulaziz Medical Cityno assertion criteria providedLikely pathogenic
(Sep 26, 2019)
germlineclinical testing

SCV001190548The Molecular Genetic Diagnosis Center, Children’s Hospital of Fudan Universitycriteria provided, single submitter
Pathogenic
(May 10, 2019)
inheritedclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001438878Pathology and Clinical Laboratory Medicine,King Fahad Medical Cityno assertion criteria provided
Likely pathogenicgermlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providedinheritedyesnot providednot providednot providednot providednot providedclinical testing
Arabgermlineyesnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

The Expanding MEGDEL Phenotype: Optic Nerve Atrophy, Microcephaly, and Myoclonic Epilepsy in a Child with SERAC1 Mutations.

Lumish HS, Yang Y, Xia F, Wilson A, Chung WK.

JIMD Rep. 2014;16:75-9. doi: 10.1007/8904_2014_322. Epub 2014 Jul 6.

PubMed [citation]
PMID:
24997715
PMCID:
PMC4221303

Mutations in the phospholipid remodeling gene SERAC1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness.

Wortmann SB, Vaz FM, Gardeitchik T, Vissers LE, Renkema GH, Schuurs-Hoeijmakers JH, Kulik W, Lammens M, Christin C, Kluijtmans LA, Rodenburg RJ, Nijtmans LG, Grünewald A, Klein C, Gerhold JM, Kozicz T, van Hasselt PM, Harakalova M, Kloosterman W, Barić I, Pronicka E, Ucar SK, et al.

Nat Genet. 2012 Jun 10;44(7):797-802. doi: 10.1038/ng.2325.

PubMed [citation]
PMID:
22683713
See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000051864.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)

Description

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.

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

From Baylor Genetics, SCV000992824.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Biochemical Molecular Genetic Laboratory,King Abdulaziz Medical City, SCV001133068.1

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

From The Molecular Genetic Diagnosis Center, Children’s Hospital of Fudan University, SCV001190548.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1inheritedyesnot providednot providednot providednot providednot providednot providednot provided

From Pathology and Clinical Laboratory Medicine,King Fahad Medical City, SCV001438878.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1Arabnot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 20, 2021

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