Submissions for variant NM_000169.3(GLA):c.1188del (p.Tyr397fs)

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Total submissions: 4

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000235570	SCV000292941	pathogenic	not provided	2015-06-30	criteria provided, single submitter	clinical testing	The c.1188delC pathogenic variant in the GLA gene has been reported previously in association with Fabry disease (Topaloglu et al., 1999). The c.1188delC variant causes a frameshift starting with codon Tyrosine 397, changes this amino acid to a Methionine residue, and creates a premature Stop codon at position 7 of the new reading frame, denoted p.Tyr397MetfsX7. This frameshift mutation replaces the typical last 33 amino acid residues in the GLA encoded protein with 6 incorrect amino acid residues resulting in a truncated protein with a possible altered function. The c.1188delC variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.1188delC as a disease-causing variant
Labcorp Genetics (formerly Invitae), Labcorp	RCV001381527	SCV001579966	pathogenic	Fabry disease	2020-08-04	criteria provided, single submitter	clinical testing	This sequence change results in a premature translational stop signal in the GLA gene (p.Tyr397Metfs*7). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 34 amino acids of the GLA protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual with Fabry disease (PMID: 10666480). ClinVar contains an entry for this variant (Variation ID: 245806). This variant disrupts the p.Pro409 amino acid residue in GLA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28768754, 31392112, 12428061, Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV001381527	SCV002054368	pathogenic	Fabry disease	2021-07-15	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000235570	SCV003826338	pathogenic	not provided	2023-01-06	criteria provided, single submitter	clinical testing

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