Submissions for variant NM_020320.5(RARS2):c.442A>G (p.Thr148Ala)

gnomAD frequency: 0.00055  dbSNP: rs143389605

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000765898	SCV000465750	uncertain significance	Pontocerebellar hypoplasia type 6	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV000489086	SCV000576546	likely pathogenic	not provided	2023-02-13	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: 31014978, 30634555, 24123792, 33972171, 29977174, 35468344)
Fulgent Genetics, Fulgent Genetics	RCV000765898	SCV000897318	uncertain significance	Pontocerebellar hypoplasia type 6	2018-10-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000765898	SCV001524598	likely pathogenic	Pontocerebellar hypoplasia type 6		criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000489086	SCV001961988	likely pathogenic	not provided	2021-09-01	criteria provided, single submitter	clinical testing
Invitae	RCV000489086	SCV003784564	uncertain significance	not provided	2022-08-20	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 148 of the RARS2 protein (p.Thr148Ala). This variant is present in population databases (rs143389605, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of pontocerebellar hypoplasia (PMID: 24123792, 30634555). ClinVar contains an entry for this variant (Variation ID: 358237). 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 disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Natera, Inc.	RCV000765898	SCV001455545	likely pathogenic	Pontocerebellar hypoplasia type 6	2020-09-16	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000489086	SCV001743430	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000489086	SCV001807058	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000489086	SCV001963884	uncertain significance	not provided		no assertion criteria provided	clinical testing