Submissions for variant NM_020320.5(RARS2):c.726A>G (p.Gln242=)

dbSNP: rs145499324

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000192607	SCV000248677	likely benign	not specified	2018-01-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000192607	SCV000514374	benign	not specified	2015-04-13	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae	RCV000872362	SCV001014161	benign	not provided	2024-01-29	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001164481	SCV001326613	likely benign	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Natera, Inc.	RCV001164481	SCV001455542	benign	Pontocerebellar hypoplasia type 6	2020-09-16	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000192607	SCV001553210	benign	not specified		no assertion criteria provided	clinical testing	The RARS2 p.Gln67Gln variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs145499324) and ClinVar (classified as a VUS by Genetics Services Laboratory, University of Chicago and as benign by GeneDx). The variant was identified in control databases in 242 of 282890 chromosomes (1 homozygous) at a frequency of 0.000855 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 227 of 24970 chromosomes (freq: 0.009091), Latino in 11 of 35440 chromosomes (freq: 0.00031), Other in 1 of 7228 chromosomes (freq: 0.000138), South Asian in 1 of 30616 chromosomes (freq: 0.000033) and European (non-Finnish) in 2 of 129194 chromosomes (freq: 0.000015), while the variant was not observed in the Ashkenazi Jewish, East Asian or European (Finnish) populations. The p.Gln67Gln variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.