Submissions for variant NM_000169.3(GLA):c.26del (p.His9fs)

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Total submissions: 4

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000627405	SCV000748399	pathogenic	not provided	2018-03-09	criteria provided, single submitter	clinical testing	The c.26delA variant in the GLA gene has been reported previously in association with Fabry disease using alternate nomenclature (Eng et al., 1994). The deletion causes a frameshift starting with codon Histidine 9, changes this amino acid to a Leucine residue and creates a premature Stop codon at position 112 of the new reading frame, denoted p.His9LeufsX112. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.26delA variant is not observed in large population cohorts (Lek et al., 2016). In summary, we interpret this variant as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000627820	SCV000748697	pathogenic	Fabry disease	2018-01-13	criteria provided, single submitter	clinical testing	This variant has been reported in individuals affected with classical Fabry disease and in one unaffected carrier female (PMID: 10916280, 15712228). For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in GLA are known to be pathogenic (PMID: 10666480, 12175777). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.His9Leufs*112) in the GLA gene. It is expected to result in an absent or disrupted protein product.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000627820	SCV001482260	pathogenic	Fabry disease	2021-02-23	criteria provided, single submitter	clinical testing	Variant summary: GLA c.26delA (p.His9LeufsX112) 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 183413 control chromosomes. c.26delA has been reported in the literature in individuals affected with Fabry Disease (Eng_2001, Rosenberg_2000, Wang_2007, Gupta_2005). These data indicate that the variant is likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab	RCV000627820	SCV002054466	pathogenic	Fabry disease	2021-07-15	criteria provided, single submitter	clinical testing

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