Submissions for variant NM_002860.4(ALDH18A1):c.2110G>A (p.Glu704Lys)

gnomAD frequency: 0.00001  dbSNP: rs758219423

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001265845	SCV001444017	uncertain significance	Inborn genetic diseases	2023-01-25	criteria provided, single submitter	clinical testing	The c.2110G>A (p.E704K) alteration is located in exon 16 (coding exon 15) of the ALDH18A1 gene. This alteration results from a G to A substitution at nucleotide position 2110, causing the glutamic acid (E) at amino acid position 704 to be replaced by a lysine (K). This change occurs in the last base pair of exon 16 (coding exon 15), which makes it likely to have some effect on normal mRNA splicing. Based on data from gnomAD, the A allele has an overall frequency of 0.001% (3/251248) total alleles studied. The highest observed frequency was 0.003% (1/34592) of Latino alleles. This nucleotide position is highly conserved in available vertebrate species. This amino acid position is highly conserved in available vertebrate species. The p.E704K amino acid is located in the gamma-glutamyl phosphate reductase domain which catalyzes the reduction and conversion to gamma-glutamyl semi-aldehyde (Coutelier, 2015). In silico splice site analysis predicts that this alteration may weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GeneDx	RCV003313204	SCV004012430	likely pathogenic	not provided	2024-12-16	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Located in the last nucleotide position of exon 16, which is part of the splice donor site; In silico analysis suggests that this missense variant does not alter protein structure/function, but splice predictors indicate that the variant may lead to abnormal gene splicing; Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26026163)
PreventionGenetics, part of Exact Sciences	RCV004528443	SCV004106397	uncertain significance	ALDH18A1-related disorder	2022-10-21	criteria provided, single submitter	clinical testing	The ALDH18A1 c.2110G>A variant is predicted to result in the amino acid substitution p.Glu704Lys. This variant occurs at the terminal nucleotide position of an exon and splicing prediction programs predict an impact on splicing at the consensus splice site (Alamut Visual Plus v.1.6.1). However, these splicing prediction programs are not equivalent to functional evidence. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-97371013-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003770383	SCV004567637	uncertain significance	Cutis laxa, autosomal dominant 3; Autosomal dominant spastic paraplegia type 9; de Barsy syndrome	2023-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 704 of the ALDH18A1 protein (p.Glu704Lys). This variant also falls at the last nucleotide of exon 16, which is part of the consensus splice site for this exon. This variant is present in population databases (rs758219423, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with ALDH18A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 985106). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.