ClinVar Miner

Submissions for variant NM_000147.4(FUCA1):c.433T>C (p.Trp145Arg) (rs150062050)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000313109 SCV000356771 uncertain significance Fucosidosis 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.
Invitae RCV000313109 SCV000812592 uncertain significance Fucosidosis 2019-09-26 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with arginine at codon 145 of the FUCA1 protein (p.Trp145Arg). The tryptophan residue is highly conserved and there is a moderate physicochemical difference between tryptophan and arginine. This variant is present in population databases (rs150062050, ExAC 0.1%). This variant has not been reported in the literature in individuals with FUCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 296890). 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: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Fulgent Genetics,Fulgent Genetics RCV000313109 SCV000896308 uncertain significance Fucosidosis 2018-10-31 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000993946 SCV001147194 uncertain significance not provided 2019-01-01 criteria provided, single submitter clinical testing
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille RCV001251773 SCV001427515 likely benign Intellectual disability 2019-01-01 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000993946 SCV001548744 uncertain significance not provided no assertion criteria provided clinical testing The FUCA1 p.Trp145Arg variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs150062050), ClinVar (classified as a VUS by Illumina Clinical Services, Invitae, and Fulgent Genetics for Fucosidosis), and LOVD 3.0. The variant was identified in control databases in 301 of 282896 chromosomes (2 homozygous) at a frequency of 0.001064 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 224 of 129196 chromosomes (freq: 0.001734), South Asian in 38 of 30616 chromosomes (freq: 0.001241), Other in 6 of 7226 chromosomes (freq: 0.00083), Latino in 19 of 35440 chromosomes (freq: 0.000536), African in 10 of 24970 chromosomes (freq: 0.000401), Ashkenazi Jewish in 2 of 10370 chromosomes (freq: 0.000193) and European (Finnish) in 2 of 25124 chromosomes (freq: 0.00008); it was not observed in the East Asian population. The p.Trp145 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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