ClinVar Miner

Submissions for variant NM_000169.3(GLA):c.376A>G (p.Ser126Gly)

gnomAD frequency: 0.00063  dbSNP: rs149391489
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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Mass General Brigham Personalized Medicine RCV000150749 SCV000198199 likely benign not specified 2017-08-06 criteria provided, single submitter clinical testing The p.Ser126Gly variant in GLA has been reported in a 12-year-old male with Fabr y disease, 1 adult female with stroke who had normal alpha-galactosidase levels, 1 female with unspecified clinical information, 1 female toddler with LVNC and arthrogryposis, 1 male toddler with neonatal onset DCM, and 2 adult females with HCM (Branton 2012, De Brabander 2013, Pasqualim 2014, LMM data). It has also be en identified in 0.07% (66/90653) of European chromosomes, including 23 hemizygo tes, in the gnomAD database (http://gnomad.broadinstitute.org; dbSNP rs149391489 ). Functional studies indicate that the p.Ser126Gly variant may reduce GLA enzym e function by 50%, but the clinical threshold and impact are not well characteri zed (Lukas 2013). A predictive model developed to determine the pathogenicity of variants in the GLA gene suggests that the p.Ser126Gly variant may not be damag ing (Riera 2015), though this information is not predictive enough to rule out p athogenicity. In summary, while the clinical significance of the p.Ser126Gly var iant is not conclusive, given the population frequency, presence of hemizygotes, inconsistency in phenotype in cases, and residual enzyme activity in functional studies, this variant is likely benign.
GeneDx RCV000782202 SCV000207807 likely benign not provided 2020-09-11 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 11889412, 29132836, 23935525, 24582695, 23219219, 26520229, 26652600, 20360539, 23306324, 23307880, 22905681, 25596309, 25382311, 28646478, 28283366, 28340804, 26990548, 29487688, 27657681, 31860127, 30477121)
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000203179 SCV000257639 uncertain significance Fabry disease 2015-06-25 criteria provided, single submitter clinical testing
Invitae RCV000203179 SCV000543769 likely benign Fabry disease 2021-12-10 criteria provided, single submitter clinical testing
Ambry Genetics RCV000621570 SCV000736899 likely benign Cardiovascular phenotype 2018-11-08 criteria provided, single submitter clinical testing Other strong data supporting benign classification
Eurofins NTD LLC (GA) RCV000150749 SCV000861548 likely benign not specified 2018-05-29 criteria provided, single submitter clinical testing
Color Health, Inc RCV000203179 SCV000914091 likely benign Fabry disease 2019-11-12 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000150749 SCV000917439 likely benign not specified 2021-10-30 criteria provided, single submitter clinical testing Variant summary: GLA c.376A>G (p.Ser126Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00033 in 183376 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in GLA causing Fabry Disease (0.00033 vs 0.005), allowing no conclusion about variant significance. c.376A>G has been identified in the literature without strong evidence for pathogenicity (e.g. Branton_2002, Colon_2017, Reisin_2018). At least one family study showed lack of co-segregation of the variant with the disease (DeBrabander_2013, Reisin_2018). In addition, a functional study found that GLA enzyme activity was reduced by ~50% in vitro, but also found that the lyso-Gb3 biomarker that is typically increased in Fabry patients was at normal levels in patient samples with the variant (Lukas_2013). Another in vitro enzyme activity study showed that the variant retained 83% of WT activity levels (Benjamin_2016). A recent study however, showed no significant reduction in enzymatic activity (Oommen_2019). Thirteen other ClinVar submitters (evaluation after 2014) cite the variant as likely benign/benign (n=9) or uncertain significance (n=4). Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics RCV000203179 SCV001141980 benign Fabry disease 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000782202 SCV001150413 uncertain significance not provided 2019-02-01 criteria provided, single submitter clinical testing
Illumina Laboratory Services,Illumina RCV000203179 SCV001327855 benign Fabry disease 2017-11-29 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Broad Institute Rare Disease Group, Broad Institute RCV000203179 SCV001422638 uncertain significance Fabry disease 2020-01-22 criteria provided, single submitter curation The p.Ser126Gly variant in GLA has been reported in 3 individuals with Fabry disease, segregated with disease in these 3 affected relatives from one family (PMID: 22905681), and has also been identified in 0.074% (69/92714) of European (non-Finnish) chromosomes, including 24 hemizygotes, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs149391489). This variant has also been reported in ClinVar as likely benign by the Laboratory for Molecular Medicine (Partners Healthcare), GeneDx, and Ambry Genetics and as a VUS by Division of Genomic Diagnostics (The Children's Hospital of Philadelphia) and Invitae (Variation ID: 163547). In vitro functional studies provide some evidence that the p.Ser126Gly variant may not impact protein function (PMID: 23935525, 11889412, 28646478). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, while the clinical significance of the p.Ser126Gly variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: BS1_supporting, BS3_supporting, PP1 (Richards 2015).
Genome-Nilou Lab RCV000203179 SCV002054819 likely benign Fabry disease 2021-07-15 criteria provided, single submitter clinical testing
Gharavi Laboratory,Columbia University RCV000782202 SCV000920681 uncertain significance not provided 2018-09-16 no assertion criteria provided research
Natera, Inc. RCV000203179 SCV001458759 likely benign Fabry disease 2020-09-16 no assertion criteria provided clinical testing

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