Submissions for variant NM_000169.3(GLA):c.758T>C (p.Ile253Thr)

dbSNP: rs727505292

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000209022	SCV001403441	likely pathogenic	Fabry disease	2019-10-17	criteria provided, single submitter	clinical testing	This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with threonine at codon 253 of the GLA protein (p.Ile253Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant has been observed in individuals affected with clinical features of Fabry disease (PMID: 27896103, 23465405, Invitae). ClinVar contains an entry for this variant (Variation ID: 180021). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Ile253 amino acid residue in GLA. Other variant(s) that disrupt this residue have been observed in individuals with GLA-related conditions (PMID: 23935525, 27657681), which suggests that this may be a clinically significant amino acid residue. This variant has been reported to affect GLA protein function (PMID: 27657681).
Revvity Omics, Revvity	RCV001781498	SCV002018452	likely pathogenic	not provided	2021-04-12	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000209022	SCV002054805	likely pathogenic	Fabry disease	2021-07-15	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000156824	SCV000206545	uncertain significance	not specified	2014-09-25	flagged submission	clinical testing	The Ile253Thr variant in GLA has been reported in 1 male with Fabry disease (Sco tt 2013). It was absent from large population studies. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the Ile253Thr va riant is uncertain.
Albrecht-Kossel-Institute, Medical University Rostock	RCV000209022	SCV000246069	pathogenic	Fabry disease	2014-01-01	no assertion criteria provided	research
Albrecht-Kossel-Institute, Medical University Rostock	RCV000209285	SCV000246070	drug response	Migalastat response	2014-01-01	no assertion criteria provided	research