Submissions for variant NM_000169.3(GLA):c.444T>G (p.Ser148Arg)

dbSNP: rs1569304190

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781430	SCV000919448	pathogenic	Fabry disease	2022-12-01	criteria provided, single submitter	clinical testing	Variant summary: GLA c.444T>G (p.Ser148Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183485 control chromosomes (gnomAD). c.444T>G has been reported in the literature in the hemizygous state in individuals affected with the classic phenotype of Fabry Disease (e.g. Eng_1997, Topaloglu_1999, Wu_2011, Schiffmann_2019, Najafian_2020). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and found that the variant results in <10% of normal activity (Wu_2011). One clinical diagnostic laboratory has submitted a clinical-significance assessment for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000781430	SCV002289001	likely pathogenic	Fabry disease	2021-04-05	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Ser148 ‚Äãamino acid residue in GLA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18205205, 15091117, 19387866, 21598360). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Experimental studies have shown that this variant affects GLA protein function (PMID: 21598360, 19387866). This variant has been observed in individual(s) with Fabry disease (PMID: 10666480). ClinVar contains an entry for this variant (Variation ID: 633251). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with arginine at codon 148 of the GLA protein (p.Ser148Arg). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and arginine.
Ambry Genetics	RCV003372841	SCV004095621	likely pathogenic	Cardiovascular phenotype	2023-08-10	criteria provided, single submitter	clinical testing	The p.S148R variant (also known as c.444T>G), located in coding exon 3 of the GLA gene, results from a T to G substitution at nucleotide position 444. The serine at codon 148 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported in individuals with Fabry disease, including individuals with classic phenotype and reduced enzyme activity (Eng CM et al. Mol Med, 1997 Mar;3:174-82; Wu X et al. Hum Mutat, 2011 Aug;32:965-77; Germain DP et al. J Med Genet, 2015 May;52:353-8; Schiffmann R et al. J Inherit Metab Dis, 2019 May;42:534-544; Najafian B et al. J Am Soc Nephrol, 2020 Apr;31:865-875; Moiseev S et al. Genes (Basel), 2022 Sep;13:[ePub ahead of print]). Additionally, an in vitro assay shows this alteration impacts protein function (Wu X et al. Hum Mutat, 2011 Aug;32:965-77). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.