ClinVar Miner

Submissions for variant NM_000169.2(GLA):c.101A>G (p.Asn34Ser) (rs104894835)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000723530 SCV000110100 pathogenic not provided 2018-06-19 criteria provided, single submitter clinical testing
Invitae RCV000011471 SCV000748700 pathogenic Fabry disease 2018-01-03 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 34 of the GLA protein (p.Asn34Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with Fabry disease (PMID: 7504405, 10649504, 7599642). ClinVar contains an entry for this variant (Variation ID: 10724). Experimental studies have shown that this missense change reduces GLA enzymatic activity (PMID: 21598360). A different missense substitution at this codon (p.Asn34Lys) has been reported in an individual affected with Fabry disease (PMID: 16595074). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000011471 SCV001360482 pathogenic Fabry disease 2019-11-19 criteria provided, single submitter clinical testing Variant summary: GLA c.101A>G (p.Asn34Ser) results in a conservative amino acid change located in the Glycoside hydrolase, family 27 domain 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 183447 control chromosomes (gnomAD). c.101A>G has been reported in the literature in multiple individuals affected with Fabry Disease (Eng_1993, Benjamin_2009, Altarescu_2001). The patients were indicated to have less than 10% alpha-Gal activity (Benjamin_2009, Altarescu_2001). These data indicate that the variant is very likely to be associated with disease. Two ClinVar submissions (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000011471 SCV000031703 pathogenic Fabry disease 1993-12-01 no assertion criteria provided literature only

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