Submissions for variant NM_002047.4(GARS1):c.562G>A (p.Val188Ile) (rs376772628)

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000513263	SCV000589331	uncertain significance	not provided	2018-08-30	criteria provided, single submitter	clinical testing	The V188I variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The V188I variant is observed in 7/30,782 (0.02%) alleles from individuals of South Asian background, in the ExAC dataset (Lek et al., 2016). The V188I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000513263	SCV000609257	uncertain significance	not provided	2017-06-01	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000513263	SCV000613383	likely benign	not provided	2017-09-25	criteria provided, single submitter	clinical testing
Invitae	RCV000819577	SCV000960245	uncertain significance	Charcot-Marie-Tooth disease, type 2	2019-03-29	criteria provided, single submitter	clinical testing	This sequence change replaces valine with isoleucine at codon 188 of the GARS protein (p.Val188Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs376772628, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with GARS-related disease. ClinVar contains an entry for this variant (Variation ID: 431819). 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Illumina Clinical Services Laboratory,Illumina	RCV001159466	SCV001321183	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	RCV001159467	SCV001321184	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.
Illumina Clinical Services Laboratory,Illumina	RCV001160833	SCV001322664	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.