Submissions for variant NM_152268.4(PARS2):c.283G>A (p.Val95Ile)

gnomAD frequency: 0.00005  dbSNP: rs147227819

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000497433	SCV000589806	uncertain significance	not provided	2022-07-21	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28077841, 29915213, 32071833, 30237576, 31130284, 31487502, 32514400, 34426522, 32533790, 32860008, 34484863, 34585293, Franz2020[paper], 34645488)
SIB Swiss Institute of Bioinformatics	RCV000779609	SCV001146819	uncertain significance	Developmental and epileptic encephalopathy, 75	2019-10-01	criteria provided, single submitter	curation	This variant is interpreted as a variant of uncertain significance for Epileptic encephalopathy, early infantile, 75, autosomal recessive. The following ACMG Tag(s) were applied: PM2, PP1, PM3.
Centogene AG - the Rare Disease Company	RCV000779609	SCV001426434	pathogenic	Developmental and epileptic encephalopathy, 75		criteria provided, single submitter	clinical testing
Pathology and Clinical Laboratory Medicine, King Fahad Medical City	RCV000779609	SCV002073813	pathogenic	Developmental and epileptic encephalopathy, 75		criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000779609	SCV002557055	pathogenic	Developmental and epileptic encephalopathy, 75	2022-02-02	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 likely mechanism of disease in this gene and is associated with developmental and epileptic encephalopathy 75 (MIM#618437). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to isoleucine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (31 heterozygotes, 0 homozygotes). (SP) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0600 - Variant is located in the annotated dimerization domain (NCBI, PMID: 29915213). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been described once as a VUS, but more recently and consistently as pathogenic and likely pathogenic in many unrelated homozygous and compound heterozygous individuals with infantile-onset epileptic encephalopathy, microcephaly, intellectual disability, seizures and/or mitochondrial disease (ClinVar, PMID: 31130284, PMID: 32071833, PMID: 30237576, PMID: 28077841, PMID: 29915213, PMID: 32533790, PMID: 32514400). (SP) 0902 - This variant has moderate evidence for segregation with disease. It was observed in a combined total of four affected siblings in two unrelated families with infantile-onset epileptic encephalopathy (PMID: 28077841, PMID: 29915213). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Invitae	RCV000497433	SCV003523297	pathogenic	not provided	2022-09-07	criteria provided, single submitter	clinical testing	This missense change has been observed in individuals with clinical features of PARS2-related conditions (PMID: 28077841, 29915213, 30237576, 31130284, 32071833, 32514400). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 432121). This variant is present in population databases (rs147227819, gnomAD 0.1%). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 95 of the PARS2 protein (p.Val95Ile).
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000779609	SCV004804954	likely pathogenic	Developmental and epileptic encephalopathy, 75	2024-03-17	criteria provided, single submitter	research
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000723278	SCV000854666	pathogenic	PARS2-related disorder	2018-04-26	no assertion criteria provided	clinical testing
OMIM	RCV000779609	SCV000916288	pathogenic	Developmental and epileptic encephalopathy, 75	2023-04-19	no assertion criteria provided	literature only