ClinVar Miner

Submissions for variant NM_000169.2(GLA):c.376A>G (p.Ser126Gly) (rs149391489)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000621570 SCV000736899 likely benign Cardiovascular phenotype 2017-09-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting benign classification
Color RCV000203179 SCV000914091 uncertain significance Fabry disease 2018-04-10 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient and conflicting evidence: This variant is a missense variant located in the TIM barrel domain of the GLA protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. Functional assays for this variant has shown a 50% reduction in enzyme activity but it is not clear if this defect is sufficient for pathogenicity (PMID 23935525). This variant has been detect in patients diagnosed with Fabry disease in the literature (PMID 11889412 20360539 23219219 23306324) but also in unaffected individuals and family members (PMID 23219219 24582695 26866599 27195818). This variant is rare in the general population (71/200450) chromosomes in the Genome Aggregation Database, gnomAD). Based on available information, this variant is classified as Variant of Uncertain Significance.
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000203179 SCV000257639 uncertain significance Fabry disease 2015-06-25 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000150749 SCV000861548 likely benign not specified 2018-05-29 criteria provided, single submitter clinical testing
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.
Gharavi Laboratory,Columbia University RCV000782202 SCV000920681 uncertain significance not provided 2018-09-16 no assertion criteria provided research
Integrated Genetics/Laboratory Corporation of America 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.
Invitae RCV000203179 SCV000543769 uncertain significance Fabry disease 2018-06-27 criteria provided, single submitter clinical testing This sequence change replaces serine with glycine at codon 126 of the GLA protein (p.Ser126Gly). The serine residue is highly conserved and there is a small physicochemical difference between serine and glycine. This variant is present in population databases (rs149391489, ExAC 0.08%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in individuals affected with Fabry disease (PMID: 11889412, 23219219, 20360539, 26866599, 23306324) but also in unaffected family members (PMID: 23219219) and in one individual with dilated cardiomyopathy (PMID: 24503780). ClinVar contains an entry for this variant (Variation ID: 163547). One experimental study has shown that this variant causes a minor catalytic defect in GLA in vitro (PMID: 23935525). However the clinical significance of this result is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
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.

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