ClinVar Miner

Submissions for variant NM_000157.4(GBA):c.115+1G>A (rs104886460)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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 type 3C; Parkinson disease, late-onset 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000790724 SCV000935506 pathogenic not provided 2020-10-07 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 and likely results in an absent or disrupted protein product. The frequency data for this variant in the population databases (rs104886460, ExAC) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This variant has been observed in individuals affected with Gaucher disease (PMID: 27682613, 23430873) and Parkinson's disease (PMID: 25653295, 20816920, 26117366). This variant is also known as IVS2+1 in the literature. 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, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants 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). 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 type 3C criteria provided, single submitter clinical testing
Myriad Women's Health, 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 Praxis fuer Humangenetik Tuebingen RCV000790724 SCV001247925 pathogenic not provided 2020-11-01 criteria provided, single submitter clinical testing
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 RCV001449616 SCV001652796 pathogenic Hereditary late onset Parkinson disease 2021-05-03 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 pathologic Gaucher disease 2011-02-01 no assertion criteria provided curation Converted during submission to Pathogenic.
Broad Institute Rare Disease Group, Broad Institute RCV000032094 SCV001422684 pathogenic Gaucher disease 2020-01-13 no assertion criteria provided 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).

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