ClinVar Miner

Submissions for variant NM_002047.4(GARS1):c.302G>A (p.Arg101His) (rs200887429)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235455 SCV000292726 uncertain significance not provided 2018-08-23 criteria provided, single submitter clinical testing The R101H variant in the GARS gene has been identified previously in the heterozygous state in two individuals with neuropathy (Antoniadi et al., 2015; Apellaniz-Ruiz et al., 2016). The R101H variant is observed in 60/126628 (0.047%) alleles from individuals of non-Finnish European background in large population cohorts (Lek et al., 2016). The R101H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, in silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret R101H as a variant of uncertain significance.
Illumina Clinical Services Laboratory,Illumina RCV001095168 SCV000468638 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 RCV000276269 SCV000468639 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 RCV000333675 SCV000468640 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.
Invitae RCV000526782 SCV000657695 uncertain significance Charcot-Marie-Tooth disease, type 2 2019-10-23 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 101 of the GARS protein (p.Arg101His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs200887429, ExAC 0.06%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in an individual affected with Charcot-Marie-Tooth disease, type 2 (CMT2) (PMID: 26392352). It was also reported in an individual who underwent genetic testing for CMT (PMID: 25614874). ClinVar contains an entry for this variant (Variation ID: 245685). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, this variant has uncertain impact on GARS function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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