ClinVar Miner

Submissions for variant NM_000169.3(GLA):c.376A>G (p.Ser126Gly) (rs149391489)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare 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 RCV000150749 SCV000207807 likely benign not specified 2018-02-09 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
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 2020-11-27 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
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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 2017-10-06 criteria provided, single submitter clinical testing Variant summary: The GLA c.376A>G (p.Ser126Gly) variant involves the alteration of a conserved nucleotide. 3/5 in silico tools predict a damaging outcome for this variant. This variant was found in 71/200453 control chromosomes, including 23 hemizygous males, at a frequency of 0.0003542 in the large control database gnomAD. Other frequently reported GLA mutations (e.g., p.Ala143Pro, Arg112Cys) are not found in gnomAD, suggesting common mutations are not found at a high frequency in the general population. The variant has been identified in numerous patients reported in the literature without evidence for pathogenicity. At least one family study found a lack of cosegregation of the variant with disease, as the variant was identified in several unaffected family members, one of whom was a male well beyond the typical age of symptom onset (De Brabander_2013). 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). Multiple clinical diagnostic laboratories/reputable databases have classified this variant with differing interpretations, including uncertain significance (3x in ClinVar) and likely benign (1x in ClinVar). Taken together, this variant is classified as likely benign.
Mendelics RCV000203179 SCV001141980 benign Fabry disease 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000782202 SCV001150413 uncertain significance not provided 2019-02-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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.
Gharavi Laboratory,Columbia University RCV000782202 SCV000920681 uncertain significance not provided 2018-09-16 no assertion criteria provided research
Broad Institute Rare Disease Group, Broad Institute RCV000203179 SCV001422638 uncertain significance Fabry disease 2020-01-22 no assertion criteria provided 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).
Natera, Inc. RCV000203179 SCV001458759 likely benign Fabry disease 2020-09-16 no assertion criteria provided clinical testing

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