Submissions for variant NM_016042.4(EXOSC3):c.238G>T (p.Val80Phe)

gnomAD frequency: 0.00093  dbSNP: rs374550999

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000117005	SCV000151126	likely pathogenic	Pontocerebellar hypoplasia type 1B	2014-01-21	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000117005	SCV000772244	pathogenic	Pontocerebellar hypoplasia type 1B	2024-10-29	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 80 of the EXOSC3 protein (p.Val80Phe). This variant is present in population databases (rs374550999, gnomAD 0.04%). This missense change has been observed in individual(s) with pontocerebellar hypoplasia (PMID: 23975261, 25809939). 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. ClinVar contains an entry for this variant (Variation ID: 129024). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt EXOSC3 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825519	SCV000966833	likely pathogenic	Pontoneocerebellar hypoplasia	2016-11-10	criteria provided, single submitter	clinical testing	The p.Val80Phe variant in EXOSC3 has been reported in 2 families with pontocereb ellar hypoplasia in the compound heterozygous state (Zanni 2013; Li 2013) and in one of the families the variant segregated in the 2 affected siblings (Zanni 20 13). This variant has been described in 0.05% (7/14042) of South Asian chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; rs 374550999). Although this variant has been seen in the general population, its f requency is low enough to be consistent with a recessive carrier frequency. Com putational prediction tools and conservation analysis suggest the variant may im pact the protein function, though this information is not predictive enough to d etermine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, the p.Val80Phe variant is likely path ogenic for pontocerebellar hypoplasia in an autosomal recessive manner based upo n allelic observations in affected individuals.
CeGaT Center for Human Genetics Tuebingen	RCV001200535	SCV001371526	likely pathogenic	not provided	2020-06-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001200535	SCV001792152	likely pathogenic	not provided	2024-12-27	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30609409, 23975261, 24524299, 29656927, 29093021, 27219052, 34532947, 34426522, 25809939)
Mendelics	RCV000117005	SCV002519618	pathogenic	Pontocerebellar hypoplasia type 1B	2022-05-04	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000117005	SCV002799081	likely pathogenic	Pontocerebellar hypoplasia type 1B	2022-04-13	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000117005	SCV005329477	pathogenic	Pontocerebellar hypoplasia type 1B	2023-05-20	criteria provided, single submitter	clinical testing	The observed missense c.238G>T(p.Val80Phe) variant in EXOSC3 gene has been reported previously in compound heterozygous state in individual(s) affected with intellectual disability, early onset spasticity, and cerebellar atrophy detects (Zanni et al., 2013). This variant is reported with the allele frequency of 0.02% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submitters). The amino acid Val at position 80 is changed to a Phe changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Val80Phe in EXOSC3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Multiple lines of computational evidence (Polyphen - Possibly Damaging, SIFT - Damaging, and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. For these reasons, this variant has been classified as Pathogenic.
GeneReviews	RCV000117005	SCV000189381	not provided	Pontocerebellar hypoplasia type 1B		no assertion provided	literature only
OMIM	RCV000117005	SCV000196098	pathogenic	Pontocerebellar hypoplasia type 1B	2013-11-01	no assertion criteria provided	literature only