Submissions for variant NM_016042.4(EXOSC3):c.395A>C (p.Asp132Ala)

gnomAD frequency: 0.00048  dbSNP: rs141138948

Total submissions: 36

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000190687	SCV000244128	pathogenic	Inborn genetic diseases	2021-08-03	criteria provided, single submitter	clinical testing	The c.395A>C (p.D132A) alteration is located in exon 2 (coding exon 2) of the EXOSC3 gene. This alteration results from an A to C substitution at nucleotide position 395, causing the aspartic acid (D) at amino acid position 132 to be replaced by an alanine (A). Based on data from the Genome Aggregation Database (gnomAD), the EXOSC3 c.395A>C alteration was observed in 0.04% (115/282766) of total alleles studied, with a frequency of 0.07% (94/129130) in the European (non-Finnish) subpopulation. The c.395A>C (p.D132A) alteration is the most common cause of EXOSC3-related pontocerebellar hypoplasia. This mutation has been reported in multiple affected individuals in the homozygous or compound heterozygous state (Wan, 2012; Biancheri, 2013; Eggens, 2014). The p.D132A alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Genetic Services Laboratory, University of Chicago	RCV000224817	SCV000247328	pathogenic	not provided	2021-10-01	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224817	SCV000281509	pathogenic	not provided	2014-06-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000224817	SCV000321607	pathogenic	not provided	2021-03-26	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: 23284067, 8147499, 22544365, 24524299, 23564332, 27777260, 25533962, 28687512, 11110791, 25326635, 30950035, 31692161, 30986545, 23975261, 31130284, 31980526, 33462000, 32645003, 31589614, 33163565, 33144682)
Fulgent Genetics, Fulgent Genetics	RCV000024366	SCV000611264	pathogenic	Pontocerebellar hypoplasia type 1B	2022-01-08	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000224817	SCV000706778	pathogenic	not provided	2017-03-08	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000024366	SCV000746484	pathogenic	Pontocerebellar hypoplasia type 1B	2017-12-03	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000024366	SCV000807246	pathogenic	Pontocerebellar hypoplasia type 1B	2017-09-01	criteria provided, single submitter	clinical testing	This mutation has been previously reported as disease-causing and was found once in our laboratory homozygous in a 7-year-old male with severe intellectual disability, hypotonia, progressive dystonia, dysmorphism, microcephaly, progressive contractures, failure to thrive, and a similarly affected sibling
Clinical Genetics, University of Leipzig	RCV000024366	SCV000886743	pathogenic	Pontocerebellar hypoplasia type 1B	2019-03-07	criteria provided, single submitter	clinical testing
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001836713	SCV000891780	pathogenic	Abnormality of the nervous system	2021-07-10	criteria provided, single submitter	clinical testing
Kariminejad - Najmabadi Pathology & Genetics Center	RCV000761614	SCV000891781	pathogenic	Hypotonia	2016-09-04	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000024366	SCV001164439	pathogenic	Pontocerebellar hypoplasia type 1B	2018-12-03	criteria provided, single submitter	research	The homozygous p.Asp132Ala variant in EXOSC3 was identified by our study in one individual with pontocerebellar hypoplasia. The p.Asp132Ala variant in EXOSC3 has been reported in 28 individuals with pontocerebellar hypoplasia, segregated with disease in 28 individuals with pontocerebellar hypoplasia with a variety of ethnic backgrounds (including Cuban, Canadian, European, Turkish, American, and Australian) and segregated with disease in 4 affected relatives from 2 families (PMID: 29656927, 22544365, 23975261, 24524299), and has been identified in 0.07279% (94/129130) of European (non-Finnish) chromosome by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs141138948). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservational analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in combination with 8 variants (including 3 loss of function variants) and in individuals with pontocerebellar hypoplasia increases the likelihood that the p.Asp132Ala variant is pathogenic (PMID: 23975261, 22544365, 24524299; Variation ID: 129024, 31690, 488793, 31689). In summary, this variant meets criteria to be classified as pathogenic for pontocerebellar hypoplasia in an autosomal recessive manner based on the predicted impact of the variant and multiple occurrences with reported pathogenic EXOSC3 variants in individuals with the disease. ACMG/AMP Criteria applied: PM2, PP3, PM3_VeryStrong, PP1_Moderate (Richards 2015).
Invitae	RCV000024366	SCV001375278	pathogenic	Pontocerebellar hypoplasia type 1B	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 132 of the EXOSC3 protein (p.Asp132Ala). This variant is present in population databases (rs141138948, gnomAD 0.07%). This missense change has been observed in individuals with pontocerebellar hypoplasia (PMID: 22544365, 23975261, 24524299, 25533962). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 31688). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on EXOSC3 protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on EXOSC3 function (PMID: 22544365, 27777260, 28687512). For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000024366	SCV001441091	pathogenic	Pontocerebellar hypoplasia type 1B	2023-12-14	criteria provided, single submitter	clinical testing	Criteria applied: PM3_VSTR,PS3_SUP,PM2_SUP,PP3
Institute of Human Genetics, Cologne University	RCV000024366	SCV001441229	pathogenic	Pontocerebellar hypoplasia type 1B	2020-09-30	criteria provided, single submitter	research
Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris	RCV000024366	SCV001519132	pathogenic	Pontocerebellar hypoplasia type 1B	2021-01-04	criteria provided, single submitter	research
New York Genome Center	RCV000024366	SCV001761026	pathogenic	Pontocerebellar hypoplasia type 1B	2020-06-30	criteria provided, single submitter	clinical testing	The c.395A>C, p.Asp132Ala missense variant identified in the EXOSC3 gene has been reported previously in multiple unrelated individuals with pontocerebellar hypoplasia type 1 [PMID: 22544365; PMID: 25149867; PMID: 23975261; PMID: 24524299; PMID: 29656927]. This variant has a frequency of 0.05% (69 heterozygous out of 143304 alleles) in gnomAD database which is low enough to be consistent with a recessive carrier frequency. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Based on the available evidence, the variant c.395A>C, p.Asp132Ala in the EXOSC3 gene is classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000224817	SCV001962180	pathogenic	not provided	2023-12-01	criteria provided, single submitter	clinical testing	EXOSC3: PM3:Very Strong, PP1:Strong, PM2
Revvity Omics, Revvity	RCV000024366	SCV002022230	pathogenic	Pontocerebellar hypoplasia type 1B	2022-07-26	criteria provided, single submitter	clinical testing
DASA	RCV000024366	SCV002061270	pathogenic	Pontocerebellar hypoplasia type 1B	2022-01-05	criteria provided, single submitter	clinical testing	The c.395A>C;p.(Asp132Ala) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 31688; PMID: 23975261; 28687512; 30986545; 23564332; 23564332; 29656927; 24524299; 27146152; 24970098; 23883322; 22544365) -. PS4.The variant is present at low allele frequencies population databases (rs141138948– gnomAD 0.004796%; ABraOM 0.000854 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Asp132Ala) was detected in trans with a pathogenic variant (PMID: 23975261; 28687512; 23564332; 23564332; 24524299; 24524299; 27146152) -PM3_very strong The variant co-segregated with disease in multiple affected family members (PMID: 23975261; 30986545; 23564332; 27146152) - PP1_strong. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000024366	SCV002061676	pathogenic	Pontocerebellar hypoplasia type 1B	2021-10-25	criteria provided, single submitter	clinical testing	PM3_VS, PP1, PP3, PM2
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000024366	SCV002512573	pathogenic	Pontocerebellar hypoplasia type 1B	2021-09-25	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS4 moderate, PM2 moderate, PM3 very strong, PP1 strong, PP3 supporting
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV000024366	SCV002559164	pathogenic	Pontocerebellar hypoplasia type 1B		criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000024366	SCV002580858	pathogenic	Pontocerebellar hypoplasia type 1B	2022-05-27	criteria provided, single submitter	clinical testing
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000024366	SCV002764687	pathogenic	Pontocerebellar hypoplasia type 1B	2021-03-10	criteria provided, single submitter	clinical testing
Center for Personalized Medicine, Children's Hospital Los Angeles	RCV003156064	SCV003845235	pathogenic	See cases	2022-12-21	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000024366	SCV003921978	pathogenic	Pontocerebellar hypoplasia type 1B	2022-03-31	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with pontocerebellar hypoplasia, type 1B (MIM#614678). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to alanine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD v2 <0.01 for a recessive condition (115 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (9 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated RNA binding S1 domain (PMID: 22544365). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic and likely pathogenic, and has been reported in many homozygous and compound heterozygous patients with pontocerebellar hypoplasia (ClinVar, PMID: 22544365). (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Lifecell International Pvt. Ltd	RCV000024366	SCV003924041	pathogenic	Pontocerebellar hypoplasia type 1B		criteria provided, single submitter	clinical testing	A Homozygote Missense variant c.395A>C in Exon 2 of the EXOSC3 gene that results in the amino acid substitution p.Asp132Ala was identified. The observed variant has a minor allele frequency of 0.00041/0.00041% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. The variant has been reported to ClinVar as Pathogenic with a status of (2 stars) criteria provided, multiple submitters, no conflicts (Variation ID 31688 as of 2022-12-24). The c.395A>C, p.Asp132Ala missense variant identified in the EXOSC3 gene has been reported previously in multiple unrelated individuals with pontocerebellar hypoplasia type 1 (Wan, Jijun et al., 2012). Functionally, the variant causes dysfunctional exosome complex (Schottmann, Gudrun et al., 2017). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.
Institute of Human Genetics, University Hospital of Duesseldorf	RCV000024366	SCV004171134	pathogenic	Pontocerebellar hypoplasia type 1B		criteria provided, single submitter	not provided
Illumina Laboratory Services, Illumina	RCV000024366	SCV004801434	pathogenic	Pontocerebellar hypoplasia type 1B	2018-12-12	criteria provided, single submitter	clinical testing	The EXOSC3 c.395A>C p.(Asp132Ala) missense variant has been identified in individuals with a phenotype consistent with pontocerebellar hypoplasia (Wan et al. 2012; Biancheri et al. 2013; Rudnik-Schöneborn et al. 2013; Zanni et al. 2013; Eggens et al. 2014; Schottman et al. 2017). At least one study indicated that a milder phenotype was observed when the variant was present in a homozygous state, but was more severe in individuals carrying the variant in a compound heterozygous state (Rudnik-Schöneborn et al. 2013). The highest frequency of this allele in the Genome Aggregation Database is 0.000904 in the European (non-Finnish) population (version 2.1.1). Morpholino knockdown of exosc3 in zebrafish embryos recapitulated the human phenotype; rescue of the abnormal phenotype was less effective with variant protein than wildtype protein (Wan et al. 2012). Functional studies in patient fibroblasts showed that the variant protein was largely retained in the cytosol and Golgi system compared with the speckled distribution in the nucleus of control cells (Schottman et al. 2017). Additionally, structural models in yeast Rrp40 demonstrate that the p.Asp132Ala variant impairs formation of a loop in the S1 domain, which is essential for interfacing with EXOSC5 and EXOSC9 (Fasken et al. 2017). Based on the collective evidence, the c.395A>C p.(Asp132Ala)variant is classified as pathogenic for pontocerebellar hypoplasia.
OMIM	RCV000024366	SCV000045659	pathogenic	Pontocerebellar hypoplasia type 1B	2013-11-01	no assertion criteria provided	literature only
GeneReviews	RCV000024366	SCV000189382	pathogenic	Pontocerebellar hypoplasia type 1B	2014-04-22	no assertion criteria provided	literature only
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000024366	SCV000536754	pathogenic	Pontocerebellar hypoplasia type 1B	2016-04-05	no assertion criteria provided	research
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000224817	SCV001926523	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000224817	SCV001957993	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000224817	SCV001974917	pathogenic	not provided		no assertion criteria provided	clinical testing