Submissions for variant NM_020320.5(RARS2):c.1366C>T (p.Arg456Cys)

gnomAD frequency: 0.00011  dbSNP: rs147844153

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000197557	SCV000252171	uncertain significance	not provided	2023-07-27	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously reported as a pathogenic or benign variant to our knowledge
Illumina Laboratory Services, Illumina	RCV000312542	SCV000465737	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.
Invitae	RCV000197557	SCV001127760	likely benign	not provided	2024-01-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271456	SCV002556250	uncertain significance	not specified	2022-06-29	criteria provided, single submitter	clinical testing	Variant summary: RARS2 c.1366C>T (p.Arg456Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00021 in 251174 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in RARS2 causing Pontocerebellar Hypoplasia, Type 6 (0.00021 vs 0.0011), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1366C>T in individuals affected with Pontocerebellar Hypoplasia, Type 6 and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as benign/likely benign, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000197557	SCV001553292	uncertain significance	not provided		no assertion criteria provided	clinical testing	The RARS2 p.Arg281Cys variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs147844153) and in ClinVar (classified as likely pathogenic by GeneDx and as a VUS by Illumina). The variant was also found in Cosmic with a FATHMM prediction of pathogenic (score=0.98). The variant was identified in control databases in 54 of 251174 chromosomes at a frequency of 0.000215 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 38 of 10070 chromosomes (freq: 0.003774), Other in 5 of 6128 chromosomes (freq: 0.000816), European (non-Finnish) in 10 of 113504 chromosomes (freq: 0.000088) and Latino in 1 of 34582 chromosomes (freq: 0.000029), while the variant was not observed in the African, East Asian, European (Finnish) and South Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Arg281 residue is conserved in mammals but not in more distantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.