Submissions for variant NM_018297.4(NGLY1):c.1481_1488del (p.His494fs)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000824894	SCV000965811	likely pathogenic	Congenital disorder of deglycosylation	2015-01-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001008628	SCV001168402	likely pathogenic	not provided	2019-03-18	criteria provided, single submitter	clinical testing	A variant that is likely pathogenic has been identified in the NGLY1 gene. The c.1481_1488delACCTTTGT variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.1481_1488delACCTTTGT variant is not observed in large population cohorts (Lek et al., 2016). The c.1481_1488delACCTTTGT variant causes a frameshift starting with codon Histidine 494, changes this amino acid to a Leucine residue and creates a premature Stop codon at position 14 of the new reading frame, denoted p.His494LeufsX14. This likely pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000824894	SCV002234563	pathogenic	Congenital disorder of deglycosylation	2022-06-28	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 666353). This variant has not been reported in the literature in individuals affected with NGLY1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.His494Leufs*14) in the NGLY1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NGLY1 are known to be pathogenic (PMID: 24651605).

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