Submissions for variant NM_001605.2(AARS1):c.904G>A (p.Ala302Thr) (rs576221121)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Clinical Services Laboratory,Illumina	RCV001094475	SCV000398679	benign	Charcot-Marie-Tooth disease, type 2N	2018-01-12	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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
GeneDx	RCV000436624	SCV000531026	uncertain significance	not provided	2016-08-18	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the AARS gene. The A302T variant has been reportedpreviously as a variant of uncertain significance in an individual with CMT1; however, further clinical informationwas not provided, and parental testing was not performed (Antoniadi et al., 2015). The A302T variant was notobserved in approximately 6,500 individuals of European and African American ancestry in the NHLBI ExomeSequencing Project, but the 1000 Genomes Project reports it was observed in 5/978 (0.5%) alleles from individuals ofSouth Asian background, indicating it may be a rare (benign) variant in this population. The A302T variant is anon-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differin polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved acrossspecies. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the proteinstructure/function. Therefore, based on the currently available information, it is unclear whether this variant is apathogenic variant or a rare benign variant.
Invitae	RCV000344744	SCV001015260	benign	Charcot-Marie-Tooth disease, type 2	2019-12-31	criteria provided, single submitter	clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000436624	SCV001245995	likely benign	not provided	2019-09-01	criteria provided, single submitter	clinical testing