Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001193046 | SCV001361595 | pathogenic | Fabry disease | 2019-07-03 | criteria provided, single submitter | clinical testing | Variant summary: GLA c.962A>G (p.Gln321Arg) results in a conservative amino acid change located in the last alpha-helix (alpha8) of the N-terminal beta/alpha-barrel region (Shabbeer_2006) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183503 control chromosomes (gnomAD). c.962A>G has been reported in the literature in multiple individuals affected with Fabry Disease (Shabbeer_2006, Lavoie_2013, Sirrs_2010). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal activity (Benjamin_2016). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Ambry Genetics | RCV002375120 | SCV002690673 | likely pathogenic | Cardiovascular phenotype | 2020-06-15 | criteria provided, single submitter | clinical testing | The p.Q321R variant (also known as c.962A>G), located in coding exon 6 of the GLA gene, results from an A to G substitution at nucleotide position 962. The glutamine at codon 321 is replaced by arginine, an amino acid with highly similar properties. This variant has been detected in multiple individuals from Fabry disease cohorts (Shabbeer J et al. Hum. Genomics, 2006 Mar;2:297-309; Sirrs S et al. Mol. Genet. Metab., 2010 Apr;99:367-73; Lavoie P et al. Anal. Chem., 2013 Feb;85:1743-52; Putko BN et al. Eur Heart J Cardiovasc Imaging, 2015 Oct;16:1129-36). Other variants affecting this codon (Q321E (c.961C>G), Q321L (c.962A>T), and Q321H (c.963G>C)) have been reported in association with Fabry disease; however, clinical details were limited in several cases (Topaloglu AK et al. Mol. Med., 1999 Dec;5:806-11; Auray-Blais C et al. Mol. Genet. Metab., 2008 Mar;93:331-40; Lukas J et al. PLoS Genet., 2013 Aug;9:e1003632). 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. |