Submissions for variant NM_000169.3(GLA):c.1033_1034del (p.Ser345fs)

dbSNP: rs398123198

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000236755	SCV000110103	pathogenic	not provided	2018-04-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000236755	SCV000292562	pathogenic	not provided	2024-05-07	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in abnormal protein length as the last 85 amino acids are replaced with 28 different amino acids, and other similar variants have been reported in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32843101, 16595074, 12938095, 34679477, 11322659, 35722479, 27896103, 8931708, 17713670, 23935525, 24236025, 35910704)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000078263	SCV000695728	pathogenic	Fabry disease	2016-06-03	criteria provided, single submitter	clinical testing	Variant summary: The GLA c.1033_1034delTC (p.Ser345Argfs) variant results in a premature termination codon, predicted to cause a truncated or absent GLA protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant is absent in 87610 control chromosomes while it was reported in several Fabry patients indicating pathogenicity. GLA activity, GLA protein levels were severely decreased in affected carriers with Lyso-Gb3 being elevated further supporting pathogenicity. Additionally, a clinical diagnostic laboratory classified this variant as Pathogenic. Taken together, this variant is classified as Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000078263	SCV001232317	pathogenic	Fabry disease	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser345Argfs*29) in the GLA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 85 amino acid(s) of the GLA protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of Fabry disease (PMID: 8931708, 23935525). This variant is also known as L344-X28-Stop and c.1029-1030delTC. ClinVar contains an entry for this variant (Variation ID: 92538). This variant disrupts a region of the GLA protein in which other variant(s) (p.Val376Profs*10) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000236755	SCV002024319	pathogenic	not provided	2021-01-19	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000078263	SCV002054380	pathogenic	Fabry disease	2021-07-15	criteria provided, single submitter	clinical testing