Submissions for variant NM_016042.4(EXOSC3):c.572G>A (p.Gly191Asp)

gnomAD frequency: 0.00001  dbSNP: rs797045567

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000625808	SCV000746365	likely pathogenic	Pontocerebellar hypoplasia type 1B	2017-12-03	criteria provided, single submitter	clinical testing
Clinical Genetics, University of Leipzig	RCV000625808	SCV000886742	likely pathogenic	Pontocerebellar hypoplasia type 1B	2019-03-07	criteria provided, single submitter	clinical testing	The variant was detected in compound heterozygous state in two siblings with pontocerebellar hypoplasia. Another missense variant c.571G>T, that leads to the same amino acid change p.(Gly191Asp) has already been described as pathogenic Halevy (2014) J Neurol 261: 2165 PubMed: 25149867 and has been functionally characterized Gillespie (2017) RNA 23: 466 PubMed: 28053271. The allele frequency of the variant c.572G>A in gnomAD is 0.008%. In summary we evaluate the variant NM_016042.3:c.572G>A, p.(Gly191Asp) as likely pathogenic based on the ACMG criteria.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000625808	SCV004272691	likely pathogenic	Pontocerebellar hypoplasia type 1B	2023-07-16	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. ClinVar contains an entry for this variant (Variation ID: 210965). 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. This missense change has been observed in individual(s) with pontocerebellar hypoplasia (PMID: 30986545, 31692161). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs797045567, gnomAD 0.002%). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 191 of the EXOSC3 protein (p.Gly191Asp).
CeGaT Center for Human Genetics Tuebingen	RCV003992226	SCV004811430	likely pathogenic	not provided	2024-03-01	criteria provided, single submitter	clinical testing	EXOSC3: PM3:Strong, PM2, PM5, PP1
Genetic Services Laboratory, University of Chicago	RCV000192511	SCV000247329	uncertain significance	not specified	2014-09-16	flagged submission	clinical testing