ClinVar Miner

Submissions for variant NM_000169.2(GLA):c.2T>C (p.Met1Thr) (rs1555987232)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000731977 SCV000859851 pathogenic not provided 2018-03-04 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000586866 SCV000695738 pathogenic Fabry disease 2016-11-03 criteria provided, single submitter clinical testing Variant summary: The GLA c.2T>C (p.Met1Thr) variant involves the alteration of a non-conserved nucleotide and results disruption of the START codon of GLA. 4/5 in silico tools predict a damaging outcome for this substitution. This variant is absent in 87229 control chromosomes while it was reported in at least two patients with Fabry disease indicating causality. GLA activity measured in a male patient showed the variant to result in ~14% activity of that of the wild type protein further supporting a pathogenic impact. Moreover, variants impacting the same codon are listed in HGMD as disease causing (M1R, M1I, M1L, M1K, M1V ) indicating the Met1 residue to be a mutational hotspot and its clinical importance. Taken together, this variant is classified as pathogenic.
Invitae RCV000586866 SCV000817130 pathogenic Fabry disease 2018-03-11 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the GLA mRNA. The next in-frame methionine is located at codon 42. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with Fabry disease (PMID: 9100224, 28672034, 28275245).  Other nucleotide substitutions affecting the initiator codon (c.2T>G and c.3G>A) have also been reported in individuals with Fabry disease (PMID: 12175777, 8807334). This variant is expected to result in an absent or disrupted protein product. If translation initiation is rescued by the downstream methionine at codon 42, this would result in loss of the signal peptide cleavage site (PMID: 8807334). For these reasons, this variant has been classified as Pathogenic.

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