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

gnomAD frequency: 0.00002  dbSNP: rs387907196

Total submissions: 22

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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000024369	SCV002238472	pathogenic	Pontocerebellar hypoplasia type 1B	2024-05-07	criteria provided, single submitter	clinical testing	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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects EXOSC3 function (PMID: 22544365, 28053271). For these reasons, this variant has been classified as Pathogenic.
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	2024-02-02	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, Medical Genetics	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).
Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire	RCV004586024	SCV005038553	pathogenic	Congenital myopathy	2024-03-01	criteria provided, single submitter	research	PS1+PM1+PM2+PP2+PP3+PP4+PP5
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
Solve-RD Consortium	RCV000024369	SCV005091396	likely pathogenic	Pontocerebellar hypoplasia type 1B	2022-06-01	no assertion criteria provided	provider interpretation	Variant confirmed as disease-causing by referring clinical team