Submissions for variant NM_000169.3(GLA):c.801G>A (p.Met267Ile)

dbSNP: rs730880451

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
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).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000627818	SCV000748695	pathogenic	Fabry disease	2019-05-15	criteria provided, single submitter	clinical testing	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). For these reasons, this variant has been classified as Pathogenic. 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. 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). This variant is not present in population databases (ExAC no frequency). 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.
Eurofins Ntd Llc (ga)	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
Genome-Nilou Lab	RCV000627818	SCV002054404	pathogenic	Fabry disease	2021-07-15	criteria provided, single submitter	clinical testing