ClinVar Miner

Submissions for variant NM_014845.5(FIG4):c.2096G>A (p.Arg699His) (rs750091928)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV001095047 SCV000459635 uncertain significance Charcot-Marie-Tooth disease, type 4J 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Clinical Services Laboratory,Illumina RCV000401287 SCV000459636 uncertain significance Amyotrophic lateral sclerosis type 11 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx RCV000481727 SCV000574264 uncertain significance not provided 2017-03-23 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the FIG4 gene. The c.2096 G>A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.2096 G>A variant is observed in 6/66,730 (0.01%) alleles from individuals of European background, in the ExAC dataset (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Several in-silico splice prediction models predict that c.2096 G>A damages the natural donor site of exon 18 which may lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. If c.2096 G>A does not effect splicing, it will result in a R699H missense variant. The R699H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000336983 SCV001198346 uncertain significance Charcot-Marie-Tooth disease type 4 2019-12-23 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 699 of the FIG4 protein (p.Arg699His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant also falls at the last nucleotide of exon 18 of the FIG4 coding sequence, which is part of the consensus splice site for this exon. This variant is present in population databases (rs750091928, ExAC 0.009%). This variant has been observed in individuals affected with amyotrophic lateral sclerosis (PMID: 29342275, 29650794). ClinVar contains an entry for this variant (Variation ID: 355043). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001196218 SCV001366768 uncertain significance Teeth, supernumerary; Abnormality of the clavicle; Congenital pseudoarthrosis of the clavicle; Aplasia/Hypoplasia of the clavicles 2019-07-26 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence on this varinat's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2. This variant was detected in heterozygous state.

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