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NM_016042.4(EXOSC3):c.92G>C (p.Gly31Ala) AND Pontocerebellar hypoplasia type 1B

Germline classification:
Pathogenic/Likely pathogenic (15 submissions)
Last evaluated:
Aug 16, 2023
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000024369.37

Allele description

NM_016042.4(EXOSC3):c.92G>C (p.Gly31Ala)

Gene:
EXOSC3:exosome component 3 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
9p13.2
Genomic location:
Preferred name:
NM_016042.4(EXOSC3):c.92G>C (p.Gly31Ala)
HGVS:
  • NC_000009.12:g.37784953C>G
  • NG_032780.1:g.5140G>C
  • NM_001002269.2:c.92G>C
  • NM_016042.4:c.92G>CMANE SELECT
  • NP_001002269.1:p.Gly31Ala
  • NP_057126.2:p.Gly31Ala
  • NP_057126.2:p.Gly31Ala
  • NC_000009.11:g.37784950C>G
  • NM_016042.2:c.92G>C
  • NM_016042.3:c.92G>C
  • Q9NQT5:p.Gly31Ala
Protein change:
G31A; GLY31ALA
Links:
UniProtKB: Q9NQT5#VAR_068505; OMIM: 606489.0004; dbSNP: rs387907196
NCBI 1000 Genomes Browser:
rs387907196
Molecular consequence:
  • NM_001002269.2:c.92G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_016042.4:c.92G>C - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Name:
Pontocerebellar hypoplasia type 1B
Identifiers:
MONDO: MONDO:0013853; MedGen: C3553449; Orphanet: 2254; OMIM: 614678

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000045662OMIM
no assertion criteria provided
Pathogenic
(Dec 1, 2013)
germlineliterature only

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

SCV000189383GeneReviews
no classification provided
not providedgermlineliterature only

SCV000247330Genetic Services Laboratory, University of Chicago
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Aug 11, 2014)
germlineclinical testing

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

SCV000680221Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München
criteria provided, single submitter

(Classification criteria August 2017)
Pathogenic
(Nov 28, 2017)
germlineclinical testing

Citation Link,

SCV001760238Genomics England Pilot Project, Genomics England
no assertion criteria provided

(ACGS Guidelines, 2016)
Likely pathogenicgermlineclinical testing

Citation Link,

SCV002238472Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Aug 16, 2023)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV002496393Provincial Medical Genetics Program of British Columbia, University of British Columbia
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Jan 1, 2022)
paternalclinical testing

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

SCV002499697Institute of Human Genetics, University Hospital Muenster
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Feb 25, 2022)
germlineclinical testing

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

SCV002580899MGZ Medical Genetics Center
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Jun 29, 2022)
germlineclinical testing

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

SCV002583327Clinical Genetics Laboratory, University Hospital Schleswig-Holstein
no assertion criteria provided
Pathogenic
(Nov 2, 2021)
germlineclinical testing

SCV002810939Fulgent Genetics, Fulgent Genetics
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Feb 16, 2022)
unknownclinical testing

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

SCV003807523Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Jul 24, 2022)
germlineclinical testing

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

SCV003823866Revvity Omics, Revvity
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Feb 19, 2022)
germlineclinical testing

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

SCV0040137663billion
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenicunknownclinical testing

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

SCV004227980Department Of Human Genetics, Institute Of Clinical And Translational Research, Biomedical Research Center, Slovak Academy Of Sciences
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenicgermlineresearch

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownyes1not providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedpaternalyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineyes91not provided2yesclinical testing, research
Prevalent among the Roma population.germlineyesnot providednot providednot providednot providednot providedliterature only

Citations

PubMed

Homozygous EXOSC3 mutation c.92G→C, p.G31A is a founder mutation causing severe pontocerebellar hypoplasia type 1 among the Czech Roma.

Schwabova J, Brozkova DS, Petrak B, Mojzisova M, Pavlickova K, Haberlova J, Mrazkova L, Hedvicakova P, Hornofova L, Kaluzova M, Fencl F, Krutova M, Zamecnik J, Seeman P.

J Neurogenet. 2013 Dec;27(4):163-9. doi: 10.3109/01677063.2013.814651. Epub 2013 Jul 25.

PubMed [citation]
PMID:
23883322

Mutations of EXOSC3/Rrp40p associated with neurological diseases impact ribosomal RNA processing functions of the exosome in S. cerevisiae.

Gillespie A, Gabunilas J, Jen JC, Chanfreau GF.

RNA. 2017 Apr;23(4):466-472. doi: 10.1261/rna.060004.116. Epub 2017 Jan 4.

PubMed [citation]
PMID:
28053271
PMCID:
PMC5340910
See all PubMed Citations (7)

Details of each submission

From OMIM, SCV000045662.3

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

Description

In 2 Czech sibs with pontocerebellar hypoplasia type 1B (PCH1B; 614678), Wan et al. (2012) identified compound heterozygosity for 2 mutations in the EXOSC3 gene: a 92G-C transversion in exon 1, resulting in a gly31-to-ala (G31A) substitution at a highly conserved residue in the N-terminal domain, and a 712T-C transition in exon 4, resulting in a trp238-to-arg (W238R; 606489.0005) substitution at a highly conserved residue in the putative RNA-binding KH domain. Another unrelated Czech boy with the disorder was homozygous for the G31A mutation. Neither mutation was found in 379 control individuals.

Schwabova et al. (2013) identified a homozygous G31A mutation in 2 unrelated Czech children of Roma descent with PCH1B. The heterozygous mutation was found in 4 (4.4%) of 90 unrelated Roma control individuals, and haplotype analysis suggested a founder effect. The patients had a severe form of the disorder, with death in the first year of life.

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

From GeneReviews, SCV000189383.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1Prevalent among the Roma population.not providednot providednot providedliterature onlynot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Genetic Services Laboratory, University of Chicago, SCV000247330.1

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

From Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München, SCV000680221.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes1bloodnot provided1not providednot providednot provided

From Genomics England Pilot Project, Genomics England, SCV001760238.1

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

From Invitae, SCV002238472.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects EXOSC3 function (PMID: 22544365, 28053271). This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 31 of the EXOSC3 protein (p.Gly31Ala). This variant is present in population databases (rs387907196, gnomAD 0.003%). This missense change has been observed in individuals with pontocerebellar hypoplasia (PMID: 22544365, 30221345). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 31691). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt EXOSC3 protein function.

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

From Provincial Medical Genetics Program of British Columbia, University of British Columbia, SCV002496393.1

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

From Institute of Human Genetics, University Hospital Muenster, SCV002499697.1

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

Description

ACMG categories: PM2,PM3,PP3,PP5

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providedbloodnot provided1not providednot providednot provided

From MGZ Medical Genetics Center, SCV002580899.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided3not providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided3not providednot providednot provided

From Clinical Genetics Laboratory, University Hospital Schleswig-Holstein, SCV002583327.1

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

From Fulgent Genetics, Fulgent Genetics, SCV002810939.1

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

From Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein, SCV003807523.1

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

Description

ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderated, PM3 strong, PP1 strong, PP3 supporting

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes1not providednot provided1not providednot providednot provided

From Revvity Omics, Revvity, SCV003823866.2

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

From 3billion, SCV004013766.1

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

Description

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.74; 3Cnet: 0.81). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000031691 / PMID: 22544365). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 22544365). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot provided1not providednot providednot provided

From Department Of Human Genetics, Institute Of Clinical And Translational Research, Biomedical Research Center, Slovak Academy Of Sciences, SCV004227980.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided3not providedyesresearch PubMed (2)

Description

The p.(Gly31Ala) variant has a low general population frequency (G = 0.000020 in gnomAD) and it has not been found in the general Slovak population (PMID: 31054297). It is frequent in Czech Roma patients (the founder effect was suggested) and 4.4 % of unrelated Czech Roma control individuals were carriers (PMID: 23883322). Slovak patients show the same or highly similar haplotype, indicating a common origin (PMID: 35852507) (there has been a close connection between the Slovak and Czech populations). Interestingly, in the study PMID: 24524299 all patients who carried this variant were of Roma/Gypsy descent, although living in different countries (Sweden and Hungary) (a common founder?) (PMID: 23284067, PMID: 23883322). The variant is in the EXOSC3 N-terminal domain that is important for intersubunit interactions: residue Gly31 has been shown tightly packed against the surface of EXOSC5, indicating its importance for EXOSC3-EXOSC5 interactions (PMID: 29093021, PMID: 27777260). Patients homozygous for this variant manifest a severe disease course including death during infancy and hypoplasia of the pons (PMID: 24524299).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided3not provided1not provided

Last Updated: Apr 15, 2024