Submissions for variant NM_000157.4(GBA1):c.1223C>T (p.Thr408Met)

gnomAD frequency: 0.00627  dbSNP: rs75548401

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	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, part of Exact Sciences	RCV000244995	SCV000305637	benign	not specified		criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000079335	SCV000780298	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	GBA1: BS2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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	Gaucher disease perinatal lethal	2018-09-28	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence favors the benign nature of this variant, however the evidence is insufficent to prove its benign nature. The following ACMG criteria were applied in classifying this variant: BP4.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001249086	SCV001423048	uncertain significance	Gaucher disease	2020-01-22	criteria provided, single submitter	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).
Genome-Nilou Lab	RCV001196545	SCV001716371	likely benign	Gaucher disease perinatal lethal	2021-05-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000079335	SCV001829252	benign	not provided	2018-12-11	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 32658388, 33281709, 32618053, 29487000, 28966932, 29842932, 30548430, 30146349, 30302829, 29396846, 28834018, 29140481, 27153395, 27648471, 28030538, 26000814, 27094865, 8774051, 22001711, 18987351, 22173904, 12694238)
Ambry Genetics	RCV000244995	SCV002756031	likely benign	not specified	2018-02-05	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
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 Laboratories, Mayo Clinic	RCV000079335	SCV000800926	benign	not provided	2017-05-17	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000079335	SCV001744398	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000079335	SCV001809374	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000079335	SCV002037727	likely benign	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001249086	SCV002086460	likely benign	Gaucher disease	2017-06-14	no assertion criteria provided	clinical testing