NM_001258392.3(CLPB):c.1159C>T (p.Arg387Ter) AND 3-methylglutaconic aciduria with cataracts, neurologic involvement, and neutropenia

Clinical significance:Pathogenic (Last evaluated: Jul 15, 2021)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
6 submissions [Details]
Record status:
current
Accession:
RCV000167543.9

Allele description [Variation Report for NM_001258392.3(CLPB):c.1159C>T (p.Arg387Ter)]

NM_001258392.3(CLPB):c.1159C>T (p.Arg387Ter)

Gene:
CLPB:caseinolytic mitochondrial matrix peptidase chaperone subunit B [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
11q13.4
Genomic location:
Preferred name:
NM_001258392.3(CLPB):c.1159C>T (p.Arg387Ter)
HGVS:
  • NC_000011.10:g.72302312G>A
  • NG_042130.2:g.137373C>T
  • NM_001258392.3:c.1159C>TMANE SELECT
  • NM_001258393.3:c.1072C>T
  • NM_001258394.3:c.1114C>T
  • NM_030813.6:c.1249C>T
  • NP_001245321.1:p.Arg387Ter
  • NP_001245322.1:p.Arg358Ter
  • NP_001245323.1:p.Arg372Ter
  • NP_110440.1:p.Arg417Ter
  • LRG_1338t1:c.1159C>T
  • LRG_1338:g.137373C>T
  • LRG_1338p1:p.Arg387Ter
  • NC_000011.9:g.72013356G>A
  • NM_030813.4:c.1249C>T
  • NM_030813.5:c.1249C>T
Protein change:
R358*; ARG417TER
Links:
OMIM: 616254.0007; dbSNP: rs200203460
NCBI 1000 Genomes Browser:
rs200203460
Molecular consequence:
  • NM_001258392.3:c.1159C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001258393.3:c.1072C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001258394.3:c.1114C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_030813.6:c.1249C>T - nonsense - [Sequence Ontology: SO:0001587]
Observations:
1

Condition(s)

Name:
3-methylglutaconic aciduria with cataracts, neurologic involvement, and neutropenia (MGCA7)
Synonyms:
3-METHYLGLUTACONIC ACIDURIA, TYPE VII
Identifiers:
MONDO: MONDO:0014561; MedGen: C4225393; Orphanet: 445038; OMIM: 616271

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000218401OMIMno assertion criteria providedPathogenic
(Feb 5, 2015)
germlineliterature only

PubMed (2)
[See all records that cite these PMIDs]

SCV000265561HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - CSER-HudsonAlphacriteria provided, single submitter
    Pathogenic
    (Sep 4, 2015)
    maternalresearch

    HA_assertions_20161101.pdf,

    SCV000328966GeneReviewsno assertion criteria providedPathogenic
    (Sep 14, 2016)
    germlineliterature only

    PubMed (2)
    [See all records that cite these PMIDs]

    Citation Link,

    SCV000821298Invitaecriteria provided, single submitter
    Pathogenic
    (Jun 28, 2018)
    germlineclinical testing

    PubMed (5)
    [See all records that cite these PMIDs]

    SCV001762982Equipe Genetique des Anomalies du Developpement, Université de Bourgognecriteria provided, single submitter
    Pathogenic
    (Jul 15, 2021)
    paternalclinical testing

    PubMed (2)
    [See all records that cite these PMIDs]

    SCV002017385PerkinElmer Genomicsno assertion criteria providedPathogenic
    (Sep 12, 2019)
    germlineclinical testing

    Summary from all submissions

    EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
    not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
    not providedpaternalunknown1not providednot providednot providednot providedclinical testing
    not providedmaternalyes1not providednot provided1not providedresearch
    not providedgermlineyesnot providednot providednot providednot providednot providedliterature only
    not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

    Citations

    PubMed

    A scoring system predicting the clinical course of CLPB defect based on the foetal and neonatal presentation of 31 patients.

    Pronicka E, Ropacka-Lesiak M, Trubicka J, Pajdowska M, Linke M, Ostergaard E, Saunders C, Horsch S, van Karnebeek C, Yaplito-Lee J, Distelmaier F, Õunap K, Rahman S, Castelle M, Kelleher J, Baris S, Iwanicka-Pronicka K, Steward CG, Ciara E, Wortmann SB; Additional individual contributors..

    J Inherit Metab Dis. 2017 Nov;40(6):853-860. doi: 10.1007/s10545-017-0057-z. Epub 2017 Jul 7.

    PubMed [citation]
    PMID:
    28687938

    CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder.

    Wortmann SB, Ziętkiewicz S, Kousi M, Szklarczyk R, Haack TB, Gersting SW, Muntau AC, Rakovic A, Renkema GH, Rodenburg RJ, Strom TM, Meitinger T, Rubio-Gozalbo ME, Chrusciel E, Distelmaier F, Golzio C, Jansen JH, van Karnebeek C, Lillquist Y, Lücke T, Õunap K, Zordania R, et al.

    Am J Hum Genet. 2015 Feb 5;96(2):245-57. doi: 10.1016/j.ajhg.2014.12.013. Epub 2015 Jan 15.

    PubMed [citation]
    PMID:
    25597510
    PMCID:
    PMC4320260
    See all PubMed Citations (7)

    Details of each submission

    From OMIM, SCV000218401.3

    #EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
    1not providednot providednot providednot providedliterature only PubMed (2)

    Description

    For discussion of the arg417-to-ter (R417X) mutation (c.1249C-T, NM_030813.4) in the CLPB gene that was found in compound heterozygous state in patients with 3-methylglutaconic aciduria with cataracts, neurologic involvement, and neutropenia (MGCA7; 616271) by Wortmann et al. (2015), see 616254.0006 and by Saunders et al. (2015), see 616254.0009.

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

    From HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - CSER-HudsonAlpha, SCV000265561.3

    #EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
    1not provided1not providednot providedresearchnot provided
    #SampleMethodObservation
    OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
    1maternalyes1not providednot provided1not providednot providednot provided

    From GeneReviews, SCV000328966.1

    #EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
    1not providednot providednot providednot providedliterature only PubMed (2)
    #SampleMethodObservation
    OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
    1germlineyesnot providednot providednot providednot providednot providednot providednot provided

    From Invitae, SCV000821298.1

    #EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
    1not providednot providednot providednot providedclinical testing PubMed (5)

    Description

    This sequence change creates a premature translational stop signal (p.Arg417*) in the CLPB gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs200203460, ExAC 0.006%). This variant has been observed to segregate with 3-methylglutaconic aciduria in several families (PMID: 25597510), as well as in several unrelated individuals affected or suspected to be affected with 3-methylglutaconic aciduria (PMID: 25597511, 27290639, 28687938). ClinVar contains an entry for this variant (Variation ID: 187786). Loss-of-function variants in CLPB are known to be pathogenic (PMID: 25597510). For these reasons, this variant has been classified as Pathogenic.

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

    From Equipe Genetique des Anomalies du Developpement, Université de Bourgogne, SCV001762982.1

    #EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
    1not provided1not providednot providedclinical testing PubMed (2)

    Description

    The patient also carries a PACS2 pathogenic variant

    #SampleMethodObservation
    OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
    1paternalunknownnot providedBloodnot provided1not providednot providednot provided

    From PerkinElmer Genomics, SCV002017385.1

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

    Last Updated: Nov 28, 2021

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