ClinVar Miner

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

gnomAD frequency: 0.00002  dbSNP: rs387907196
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 20
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000024369 SCV000247330 pathogenic Pontocerebellar hypoplasia type 1B 2014-08-11 criteria provided, single submitter clinical testing
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München RCV000024369 SCV000680221 pathogenic Pontocerebellar hypoplasia type 1B 2017-11-28 criteria provided, single submitter clinical testing
Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine RCV000853550 SCV000995079 pathogenic Fetal akinesia deformation sequence 1; Lissencephaly; Microcephaly; Abnormal cerebellum morphology; Paucity of anterior horn motor neurons; Severe intrauterine growth retardation; Hypoplasia of the pons 2019-10-09 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV001092265 SCV001248685 pathogenic not provided 2020-01-01 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV001092265 SCV001447486 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital RCV001092265 SCV001450345 pathogenic not provided 2016-11-18 criteria provided, single submitter clinical testing
GeneDx RCV001092265 SCV001801416 pathogenic not provided 2022-05-02 criteria provided, single submitter clinical testing Published yeast functional studies demonstrate a damaging effect with impaired pre-rRNA processing (Gillespie et al., 2017); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30986545, 27777260, 27876572, 23883322, 28053271, 29096039, 22544365, 30221345, 30025162, 29656927, 34426522, 31589614, 31770597, 24524299)
Invitae RCV000024369 SCV002238472 pathogenic Pontocerebellar hypoplasia type 1B 2023-08-16 criteria provided, single submitter clinical testing 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.
Provincial Medical Genetics Program of British Columbia, University of British Columbia RCV000024369 SCV002496393 pathogenic Pontocerebellar hypoplasia type 1B 2022-01-01 criteria provided, single submitter clinical testing
Institute of Human Genetics, University Hospital Muenster RCV000024369 SCV002499697 likely pathogenic Pontocerebellar hypoplasia type 1B 2022-02-25 criteria provided, single submitter clinical testing ACMG categories: PM2,PM3,PP3,PP5
MGZ Medical Genetics Center RCV000024369 SCV002580899 pathogenic Pontocerebellar hypoplasia type 1B 2022-06-29 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000024369 SCV002810939 pathogenic Pontocerebellar hypoplasia type 1B 2022-02-16 criteria provided, single submitter clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV000024369 SCV003807523 pathogenic Pontocerebellar hypoplasia type 1B 2022-07-24 criteria provided, single submitter clinical testing ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderated, PM3 strong, PP1 strong, PP3 supporting
Revvity Omics, Revvity RCV000024369 SCV003823866 pathogenic Pontocerebellar hypoplasia type 1B 2022-02-19 criteria provided, single submitter clinical testing
3billion RCV000024369 SCV004013766 likely pathogenic Pontocerebellar hypoplasia type 1B criteria provided, single submitter clinical testing 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.
Department Of Human Genetics, Institute Of Clinical And Translational Research, Biomedical Research Center, Slovak Academy Of Sciences RCV000024369 SCV004227980 pathogenic Pontocerebellar hypoplasia type 1B criteria provided, single submitter research 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).
OMIM RCV000024369 SCV000045662 pathogenic Pontocerebellar hypoplasia type 1B 2013-12-01 no assertion criteria provided literature only
GeneReviews RCV000024369 SCV000189383 not provided Pontocerebellar hypoplasia type 1B no assertion provided literature only
Genomics England Pilot Project, Genomics England RCV000024369 SCV001760238 likely pathogenic Pontocerebellar hypoplasia type 1B no assertion criteria provided clinical testing
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein RCV000024369 SCV002583327 pathogenic Pontocerebellar hypoplasia type 1B 2021-11-02 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.