Submissions for variant NM_000157.4(GBA1):c.1603C>T (p.Arg535Cys)

gnomAD frequency: 0.00001  dbSNP: rs747506979

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001175549	SCV001339173	pathogenic	Gaucher disease	2020-03-01	criteria provided, single submitter	clinical testing	Variant summary: GBA c.1603C>T (p.Arg535Cys) also widely reported as p.Arg496Cys, results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 172274 control chromosomes. c.1603C>T has been well reported in the literature in multiple individuals from diverse ethnicities affected with Gaucher Disease (example, Kawame_1992, Karaca_2012, Ankleshwaria_2014 and Feng_2018). These data indicate that the variant is very likely to be associated with disease. No experimental evidence demonstrating an impact on protein function was ascertained. Although at-least one publication reported its identification in a enzymatically and clinically diagnosed Gaucher disease homozygous individual with no primary data provided (Kawame_1992). One researcher has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. This submitter cites an overlapping publication utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000417294	SCV001422766	pathogenic	Gaucher disease type I	2020-01-22	criteria provided, single submitter	curation	The p.Arg535Cys variant in GBA has been reported at least 10 individuals with Gaucher disease (PMID: 27865684, 30637984, 30764785) and has been identified in 0.004% (1/24272) of South Asian chromosomes and 0.004% (1/25702) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs747506979). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (VariationID: 242383) as likely pathogenic by the Institute of Human Genetics. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. One additional pathogenic variant, resulting in a different amino acid change at the same position, p.Arg535His, has been reported in association with the disease in the literature and ClinVar, supporting that a change at this position may not be tolerated (PMID: 17059888, 24756352, 17427031, 20629126, 7655857, 28947706, 23430543, 8432537; VariationID: 4311). The phenotype of an individual compound heterozygous for this variant is highly specific for Gaucher disease based on the levels of beta-glucosidase detected in the BGL test being significantly below 8.7 nmol/mg/h consistent with disease (PMID: 27865684). Additionally, the homozygous occurrence of this variant in two affected individuals and the presence of this variant in combination with reported pathogenic variants (VariationID: 4288, 4295, 4290; PMID: 30764785, 27865684, 30637984) and in five individuals with Gaucher disease increases the likelihood that the p.Arg535Cys variant is pathogenic. In summary, this variant meets criteria to be classified as pathogenic for Gaucher disease in an autosomal recessive manner based on the detection of the variant in combination with other pathogenic variants in affected individuals, the presence of another pathogenic variant at the same location, and the presence of the variant in an individual with a phenotype specific for the disease. ACMG/AMP Criteria applied: PM3_very-Strong, PM2, PM5, PP4 (Richards, 2015).
Revvity Omics, Revvity	RCV001782727	SCV002018399	pathogenic	not provided	2023-06-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001782727	SCV002228247	pathogenic	not provided	2022-09-19	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg535 amino acid residue in GBA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16293621, 27735925). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GBA protein function. ClinVar contains an entry for this variant (Variation ID: 242383). This variant is also known as p.Arg496Cys or R496C. This missense change has been observed in individual(s) with Gaucher disease and/or Parkinson's disease (PMID: 1487244, 24522292, 28727984, 29140481). This variant is present in population databases (rs747506979, gnomAD 0.004%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 535 of the GBA protein (p.Arg535Cys).
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000417294	SCV000281966	likely pathogenic	Gaucher disease type I	2016-06-10	no assertion criteria provided	research	USG abdomen s/o. storage disease; Bone-marrow s/o. Storage disease; Anaemia (Hb: 8.6 g%); Plasma Chitotriosidase: 11755.7 nmol/hr/ml plasma (N.R.: 28.66 - 62.94); Beta-Glucosidase: 1.45 nmol/hr/mg protein (N.R.: 4.0 - 32.0)
Natera, Inc.	RCV001175549	SCV002086446	pathogenic	Gaucher disease	2020-05-04	no assertion criteria provided	clinical testing