Submissions for variant NM_002860.4(ALDH18A1):c.2293C>T (p.Arg765Ter)

gnomAD frequency: 0.00001  dbSNP: rs1462559161

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000578985	SCV000681072	likely pathogenic	not provided	2017-11-02	criteria provided, single submitter	clinical testing	The R765X variant in the ALDH18A1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is predicted to cause loss of normal protein function through protein truncation. The R765X variant is not observed in large population cohorts (Lek et al., 2016). We interpret R765X as a likely pathogenic variant.
CeGaT Center for Human Genetics Tuebingen	RCV000578985	SCV001148051	uncertain significance	not provided	2019-04-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001330992	SCV001522872	likely pathogenic	Cutis laxa, autosomal dominant 3		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003767254	SCV004607510	uncertain significance	Cutis laxa, autosomal dominant 3; Autosomal dominant spastic paraplegia type 9; de Barsy syndrome	2024-12-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg765*) in the ALDH18A1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 31 amino acid(s) of the ALDH18A1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with multiple congenital anomalies (PMID: 33144682). ClinVar contains an entry for this variant (Variation ID: 489087). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.