ClinVar Miner

Submissions for variant NM_000157.4(GBA):c.1342G>C (p.Asp448His) (rs1064651)

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000079338 SCV000224864 pathogenic not provided 2016-04-20 criteria provided, single submitter clinical testing
GeneDx RCV000079338 SCV000329943 pathogenic not provided 2018-10-26 criteria provided, single submitter clinical testing The D448H variant in the GBA gene has been reported previously (as D409H due to alternate nomenclature) in multiple individuals with Gaucher disease both in the homozygous state, as well as in the heterozygous state in the presence of a second GBA variant (Eyal et al., 1990; Chabas et al., 1995; Cindik et al., 2010). Studies in fibroblasts from an affected individual, as well as sf9 cell lines with the D448H variant, revealed significantly reduced enzyme activity (Grace et al., 1994; Chabas et al., 1995). Additional studies of over-expression of the D448H variant in PC12 and MES23.5 cell lines suggest that impaired enzyme activity correlates to an increased risk of Parkinson's disease (Cullen et al., 2011). The D448H variant is observed in 7/33462 (0.021%) alleles from individuals of Latino background in large population cohorts, and no individuals are reported to be homozygous (Lek et al., 2016). The D448H variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. We interpret D448H as a pathogenic variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000055773 SCV000697581 pathogenic Gaucher disease 2016-12-23 criteria provided, single submitter clinical testing Variant summary: The GBA c.1342G>C (p.Asp448His) variant, alternatively also known as D409H, involves the alteration of a conserved nucleotide, is located in Glycoside hydrolase superfamily domain (InterPro) and is predicted to be damaging by 2/4 in silico tools. This variant was found in 11/100268 control chromosomes at a frequency of 0.0001097, which does not exceed the estimated maximal expected allele frequency of a pathogenic GBA variant (0.005). This variant is widely reported as a pathogenic variant with consistent genotype-phenotype and functional study data. The allele frequency of this variant from a cohort of all GD patients (n=436) registered in Portugal and Spain was 28/872 (3.3%). The variant typically causes severe form of disease (i.e. GD type 3) when present in homozygous state. Another missense variant at this residue D448V is also a known pathogenic variant. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000762853 SCV000893213 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 RCV000079338 SCV000964937 pathogenic not provided 2020-09-28 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with histidine at codon 448 of the GBA protein (p.Asp448His). The aspartic acid residue is moderately conserved and there is a moderate physicochemical difference between aspartic acid and histidine. The frequency data for this variant in the population databases (rs1064651, 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 and families affected with Gaucher disease (PMID: 11992489, 25946768, 8544197, 19816973, 15146461) as well as individuals with Parkinson's disease (PMID: 20816920, 21742527, 21745757, 24126159, 27717005) and dementia with lewy bodies (PMID: 27312774, 23588557). This variant is also known as p.Asp409His or D409H in the literature. ClinVar contains an entry for this variant (Variation ID: 4293, 4334). Experimental studies have shown that this missense change disrupts the GBA enzyme activity (PMID: 8294487, 21257328, 16293621). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV001004114 SCV001162845 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. RCV000004523 SCV001194232 likely pathogenic Gaucher disease type I 2019-12-20 criteria provided, single submitter clinical testing NM_001005741.2(GBA):c.1342G>C(D448H) is classified as likely pathogenic in the context of Gaucher disease. Sources cited for classification include the following: PMID 15146461, 2269438, 11992489, 16293621, 19816973, 11359469 and 8544197. Classification of NM_001005741.2(GBA):c.1342G>C(D448H) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000079338 SCV001247920 pathogenic not provided 2020-02-01 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000004526 SCV001366383 pathogenic Gaucher disease, perinatal lethal 2020-04-01 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PS4,PM2,PM3,PP3,PS1_SUP.
Fulgent Genetics,Fulgent Genetics RCV001449612 SCV001652792 pathogenic Hereditary late onset Parkinson disease 2021-05-03 criteria provided, single submitter clinical testing
OMIM RCV000004522 SCV000024696 pathogenic Gaucher disease type 3C 2008-07-01 no assertion criteria provided literature only
OMIM RCV000004523 SCV000024697 pathogenic Gaucher disease type I 2008-07-01 no assertion criteria provided literature only
OMIM RCV000004524 SCV000024698 pathogenic Gaucher disease type II 2008-07-01 no assertion criteria provided literature only
OMIM RCV000004525 SCV000024699 pathogenic Gaucher disease type III 2008-07-01 no assertion criteria provided literature only
OMIM RCV000004526 SCV000024700 pathogenic Gaucher disease, perinatal lethal 2008-07-01 no assertion criteria provided literature only
GeneReviews RCV000055773 SCV000086732 pathologic Gaucher disease 2013-09-19 no assertion criteria provided curation Converted during submission to Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000079338 SCV000800924 pathogenic not provided 2017-05-10 no assertion criteria provided clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV000055773 SCV001423055 pathogenic Gaucher disease 2020-01-22 no assertion criteria provided curation The p.Asp448His variant in GBA has been reported in at least 33 individuals with Gaucher disease (PMID: 17427031, 8213821, 18586596, 11933202, 19816973) and has been identified in 0.020% (7/34432) of Latino chromosomes by the Genome Aggregation Database (gnomAD,; dbSNP rs1064651). 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: 4293) as likely pathogenic by Counsyl and as pathogenic by EGL Genetic Diagnostics, GeneDx, Integrated Genetics, Fulgent Genetics, Mayo Clinic Genetic Testing Laboratories, and OMIM. Animal models in mice have shown that this variant causes Gaucher disease based on visceral disease and decreased beta-glucosidase levels (PMID: 16061944). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional likely pathogenic variant, resulting in a different amino acid change at the same position, p.Asp448Val, has been reported in association with disease in the literature and ClinVar, slightly supporting that a change at this position may not be tolerated (PMID: 2349952, 17509920, 28223512, 2508065; Variation ID: 4294). Additionally, the homozygous occurrence of this variant in at least 23 individuals with Gaucher disease and the presence of this variant in combination with reported pathogenic variants in at least 9 individuals with Gaucher disease (VariationID: 4327, 4288, 03445; PMID: 17427031, 8213821, 18586596, 11933202, 19816973) increases the likelihood that the p.Asp448His 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 multiple occurrences of the variant in affected individuals who are homozygous or compound heterozygous with another pathogenic variant, mouse models showing the variant to be damaging, and computational tools. ACMG/AMP Criteria applied: PM3_very-strong, PS3, PM2_supporting, PM5_supporting, PP3 (Richards 2015).

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