Submissions for variant NM_000157.4(GBA1):c.115+1G>A

gnomAD frequency: 0.00006  dbSNP: rs104886460

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000790724	SCV000228922	pathogenic	not provided	2015-09-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000032094	SCV000697575	pathogenic	Gaucher disease	2016-08-11	criteria provided, single submitter	clinical testing	Variant summary: The GBA c.115+1G>A variant involves the alteration of a conserved intronic splice-site nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict that this variant eliminates the splicing donor site, which has been confirmed in one patient using cDNA sequencing. This variant has been reported in numerous patients with Gaucher disease. This variant was found in 14/121336 control chromosomes at a frequency of 0.0001154, which does not exceed the estimated maximal expected allele frequency of a pathogenic GBA variant (0.005). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000762856	SCV000893216	pathogenic	Lewy body dementia; Gaucher disease type I; Gaucher disease type II; Gaucher disease type III; Gaucher disease perinatal lethal; Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome; Parkinson disease, late-onset	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000790724	SCV000935506	pathogenic	not provided	2022-10-28	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 3 of the GBA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in GBA are known to be pathogenic (PMID: 9153297, 10079102, 10796875, 11783951). The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. Disruption of this splice site has been observed in individuals with Gaucher disease and/or Parkinson disease (PMID: 20816920, 23430873, 25653295, 26117366, 27682613). This variant is also known as IVS2+1. ClinVar contains an entry for this variant (Variation ID: 93445). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV001004137	SCV001162868	pathogenic	Gaucher disease type I; Gaucher disease type II; Gaucher disease type III; Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome		criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000177098	SCV001194067	pathogenic	Gaucher disease type I	2019-12-09	criteria provided, single submitter	clinical testing	NM_001005741.2(GBA):c.115+1G>A(aka IVS2+1G>A) is classified as pathogenic in the context of Gaucher disease and can be associated with Type 1, 2 or 3. Sources cited for classification include the following: PMID 12204005, 25127542, 1558964, 11933202 and 20729108. Classification of NM_001005741.2(GBA):c.115+1G>A(aka IVS2+1G>A) is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
CeGaT Center for Human Genetics Tuebingen	RCV000790724	SCV001247925	pathogenic	not provided	2024-06-01	criteria provided, single submitter	clinical testing	GBA1: PVS1, PS4:Moderate, PM2:Supporting
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000032094	SCV001422684	pathogenic	Gaucher disease	2020-01-13	criteria provided, single submitter	curation	The c.115+1G>A variant in GBA has been reported in at least 4 individuals with Gaucher disease (PMID: 10649495, 23430873, 25127542) and has been identified in 0.019% (2/10370) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs104886460). 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: 93445) as pathogenic by EGL Genetic Diagnostics, Counsyl, Integrated Genetics, Fulgent Genetics, and OMIM. This variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the GBA gene is an established disease mechanism in autosomal recessive Gaucher disease. The presence of this variant in combination with reported pathogenic variants and in 3 individuals with Gaucher disease increases the likelihood that the c.115+1G>A variant is pathogenic (VariationID: 4288, 4290; PMID: 10649495, 23430873). In summary, this variant meets criteria to be classified as pathogenic for Gaucher disease in an autosomal recessive manner based on the prediction that the variant will cause loss-of-function and the occurrences of the variant in combination with other pathogenic variants in affected individuals. ACMG/AMP Criteria applied: PVS1, PM3, PM2_supporting (Richards 2015).
Institute of Human Genetics, University of Leipzig Medical Center	RCV001253701	SCV001429549	likely pathogenic	Parkinson disease, late-onset	2016-09-27	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001253701	SCV001652796	pathogenic	Parkinson disease, late-onset	2021-05-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000790724	SCV001763816	pathogenic	not provided	2024-07-25	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 22975760, 20816920, 25653295, 25525159, 21228398, 1558964, 23430873, 21700325, 35861108, 33473340, 26689913, 26117366, 27682613, 31561936, 33176831, 36637080, 32191290, 33402667, 33301762, 34867278, 34930372, 35747619, 34308104, 35242582, 35845720, 37198191, 35639160, 36879366, 33972609, 32613234)
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV001253701	SCV001994778	pathogenic	Parkinson disease, late-onset	2021-10-18	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000790724	SCV002503250	pathogenic	not provided	2021-04-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004019534	SCV002756316	pathogenic	not specified	2017-01-31	criteria provided, single submitter	clinical testing	The c.115+1G>A (also known as IVS2+1G>A) intronic pathogenic mutation from a G to A substitution one nucleotide after coding exon 2 of the GBA gene. This mutation has been reported in multiple patients with Gaucher disease, confirmed with decreased beta-glucosidase activity (Beutler E et al. Blood, 1992 Apr;79:1662-6; Yoshida S et al. Pediatr Int, 2016 Sep;58:946-9). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Revvity Omics, Revvity	RCV000790724	SCV003825838	pathogenic	not provided	2023-08-10	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000790724	SCV005198013	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
OMIM	RCV000177098	SCV000024719	pathogenic	Gaucher disease type I	2000-01-01	no assertion criteria provided	literature only
OMIM	RCV000004546	SCV000024720	pathogenic	Gaucher disease type II	2000-01-01	no assertion criteria provided	literature only
GeneReviews	RCV000032094	SCV000054468	not provided	Gaucher disease		no assertion provided	literature only
Natera, Inc.	RCV000032094	SCV002086486	pathogenic	Gaucher disease	2017-03-17	no assertion criteria provided	clinical testing