Submissions for variant NM_002047.4(GARS1):c.1100A>G (p.Asn367Ser) (rs192443850)

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Clinical Services Laboratory,Illumina	RCV000302958	SCV000468677	benign	Distal hereditary motor neuronopathy type 5	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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Clinical Services Laboratory,Illumina	RCV001095236	SCV000468678	likely benign	Charcot-Marie-Tooth disease type 2D	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.
Illumina Clinical Services Laboratory,Illumina	RCV000267692	SCV000468679	benign	Distal spinal muscular atrophy	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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
GeneDx	RCV000445234	SCV000519892	uncertain significance	not specified	2016-10-18	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the GARS gene. The N367S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The N367S variant is observed in 35/66,730 (0.05%) alleles from individuals of European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The N367S variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Asparagine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV000558968	SCV000657686	likely benign	Charcot-Marie-Tooth disease, type 2	2019-12-31	criteria provided, single submitter	clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen	RCV001171985	SCV001334909	likely benign	not provided	2020-03-01	criteria provided, single submitter	clinical testing
Inherited Neuropathy Consortium	RCV001027470	SCV001190040	likely pathogenic	Charcot-Marie-Tooth disease		no assertion criteria provided	provider interpretation