Submissions for variant NM_000169.3(GLA):c.679C>T (p.Arg227Ter)

gnomAD frequency: 0.00001  dbSNP: rs104894841

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000157897	SCV000110133	pathogenic	not provided	2018-05-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000157897	SCV000207828	pathogenic	not provided	2021-02-03	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate this variant reduced GLA activity to 2% of controls (Shimotori et al., 2008); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 25974833, 18205205, 25439755, 23935525, 25525159, 26047621, 28728877, 31542871, 8395937, 30477121, 31411008, 33072517, 33204599, 33673806)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000011479	SCV000965451	pathogenic	Fabry disease	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg227*) in the GLA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GLA are known to be pathogenic (PMID: 10666480, 12175777). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Fabry disease and hypertrophic cardiomyopathy (PMID: 8395937, 18205205, 25439755, 26047621). ClinVar contains an entry for this variant (Variation ID: 10733). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000011479	SCV001363733	pathogenic	Fabry disease	2020-08-21	criteria provided, single submitter	clinical testing	Variant summary: GLA c.679C>T (p.Arg227X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 183590 control chromosomes (gnomAD and publication data). c.679C>T has been reported in the literature in multiple individuals affected with Fabry Disease (Ashley_2001, Davies_1993, Germain_2002, Gomez_2012, Nakano_2013, Giugliani_2013). These data indicate that the variant is very likely to be associated with disease. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000157897	SCV002024819	pathogenic	not provided	2023-07-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000011479	SCV002054419	pathogenic	Fabry disease	2021-07-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000011479	SCV002811113	pathogenic	Fabry disease	2021-07-13	criteria provided, single submitter	clinical testing
OMIM	RCV000011479	SCV000031711	pathogenic	Fabry disease	1993-12-01	no assertion criteria provided	literature only
Blueprint Genetics	RCV000011479	SCV000188767	pathogenic	Fabry disease	2014-01-30	no assertion criteria provided	clinical testing