ClinVar Miner

Submissions for variant NM_000157.4(GBA):c.1223C>T (p.Thr408Met) (rs75548401)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000244995 SCV000111205 benign not specified 2016-05-09 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000079335 SCV000281415 likely benign not provided 2015-12-23 criteria provided, single submitter clinical testing Converted during submission to Likely benign.
PreventionGenetics,PreventionGenetics RCV000244995 SCV000305637 benign not specified criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000079335 SCV000780298 likely benign not provided 2020-04-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000244995 SCV000919416 benign not specified 2018-01-02 criteria provided, single submitter clinical testing Variant summary: The GBA c.1223C>T (p.Thr408Met, also known as Thr369Met) variant located in the glycosyl hydrolase family 30, TIM-barrel domain (via InterPro) involves the alteration of a non-conserved nucleotide and 2/3 in silico tools predict a benign outcome for this variant (SNPsandGO and MutationTaster not captured due to low reliability index and p-value). This variant was found in 1708/277314 (7 homozygotes) control chromosomes (gnomAD and publication controls) at a frequency of 0.0061591, which is approximately 1 times the estimated maximal expected allele frequency of a pathogenic GBA variant (0.005), suggesting this variant is likely a benign polymorphism. Multiple publications have cited the variant in affected individuals including a co-occurrence with another pathogenic GBA variant, D409H (also known as D448H - scored DV)(Hodanova_1999). Another publication, Walker_2003, cites the variant, T369M, as a polymorphism. A publication, Hodanova_2003, does indicate the variant could cause a functional impact but the authors state that at most would be a mild mutation even on the verge of a polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as "likely benign/benign." Taken together, this variant is classified as benign.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001196545 SCV001367153 uncertain significance Apathy; Tremor; Easy fatigability; CNS demyelination; Dermal translucency 2018-09-28 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,BP4. This variant was detected in homozygous state.
DST/NWU Preclinical Drug Development Platform,North-West University RCV000416597 SCV000245439 uncertain significance Parkinson disease, late-onset 2015-09-08 no assertion criteria provided research
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000079335 SCV000800926 benign not provided 2017-05-17 no assertion criteria provided clinical testing
Broad Institute Rare Disease Group,Broad Institute RCV001249086 SCV001423048 uncertain significance Gaucher disease 2020-01-22 no assertion criteria provided curation The p.Thr408Met variant in GBA has been reported in at least 4 individuals with Gaucher disease (PMID: 12734541, 12694238, 10796875) and has been identified in 0.992% (249/25102) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs75548401). This variant has also been reported in ClinVar (VariationID: 93447) as a VUS by DST/NWU Preclinical Drug Development Platform, as likely benign by CeGaT Praxis fuer Humangnetik Tuebingen and Children's Mercy Hospital and Clinics, and as benign by PreventionGenetics, EGL Genetic Diagnostics, and Integrated Genetics. In vitro functional studies provide some evidence that the p.Thr408Met variant may not impact protein function (PMID: 12734541). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. This variant was reported with a reported pathogenic variant in an unknown phase in 2 individuals with Gaucher disease (VariationID: 4290; PMID: 12734541, 10796875). However, this variant was also found in cis with other pathogenic variants, suggesting that it may not cause disease (VariationID: 65570, 4293; PMID: 12734541, 12694238). In summary, the clinical significance of the p.Thr408Met variant is uncertain. ACMG/AMP Criteria applied: BS1, PP3, BP2, BS3_supporting (Richards 2015).

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