ClinVar Miner

Submissions for variant NM_000169.2(GLA):c.801G>A (p.Met267Ile) (rs730880451)

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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 RCV000157900 SCV000860476 pathogenic not provided 2018-03-21 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000627818 SCV000893812 pathogenic Fabry disease 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000157900 SCV000207831 pathogenic not provided 2014-01-18 criteria provided, single submitter clinical testing The M267I mutation in the GLA gene has been reported in a single patient with Fabry disease who was hemizygous for the mutation and had a plasma alpha-Gal A activity of 0.2U/ml (Topaloglu A et al., 1999). Other mutations affecting the same residue (M267R, M267T) as well as mutations in neighboring residues (D266V, D266E, L268S) have been reported in association with Fabry disease, further supporting the functional importance of this residue and this region of the protein. Furthermore, the M267I mutation was not observed inapproximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, M267I in the GLA gene is interpreted as a disease-causing mutation. The variant is found in HCM panel(s).
Invitae RCV000627818 SCV000748695 pathogenic Fabry disease 2017-12-12 criteria provided, single submitter clinical testing This sequence change replaces methionine with isoleucine at codon 267 of the GLA protein (p.Met267Ile). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and isoleucine. This variant also falls at the last nucleotide of exon 5 of the GLA coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with Fabry disease (PMID: 10666480, 11668641, Invitae). ClinVar contains an entry for this variant (Variation ID: 180842). Experimental studies have shown that this missense change has a moderate effect on GLA protein aggregation but results in a reduction of GLA enzymatic activity in vitro (PMID: 22773828). Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.

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