Submissions for variant NM_001080442.3(SLC38A8):c.848A>C (p.Asp283Ala)

gnomAD frequency: 0.00024  dbSNP: rs139373929

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413331	SCV000490813	likely pathogenic	not provided	2016-01-26	criteria provided, single submitter	clinical testing	The D283A variant in the SLC38A8 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The D283A variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The D283A variant is a non-conservative amino acid substitution that occurs at a position which is highly conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. A single amino acid deletion of an adjacent residue (A282del) has been reported in the compound heterozygous state in two sisters affected with foveal hypoplasia and optic nerve decussation defects, supporting the functional importance of this region of the protein (Poulter et al., 2013). The D283A variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Undiagnosed Diseases Network, NIH	RCV000991179	SCV001432155	uncertain significance	Foveal hypoplasia - optic nerve decussation defect - anterior segment dysgenesis syndrome	2020-04-08	criteria provided, single submitter	clinical testing	This variant was observed in a patient with foveal hypoplasia and a second likely pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000413331	SCV002300948	pathogenic	not provided	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 283 of the SLC38A8 protein (p.Asp283Ala). This variant is present in population databases (rs139373929, gnomAD 0.6%). This missense change has been observed in individuals with autosomal recessive foveal hypoplasia (PMID: 28546991, 29345414, 33498813; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 372508). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SLC38A8 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000991179	SCV004238665	likely pathogenic	Foveal hypoplasia - optic nerve decussation defect - anterior segment dysgenesis syndrome	2023-06-02	criteria provided, single submitter	clinical testing
Reproductive Health Research and Development, BGI Genomics	RCV000991179	SCV001142464	uncertain significance	Foveal hypoplasia - optic nerve decussation defect - anterior segment dysgenesis syndrome	2020-01-06	no assertion criteria provided	curation	NM_001080442.1:c.848A>C in the SLC38A8 gene has an allele frequency of 0.006 in Ashkenazi Jewish subpopulation in the gnomAD database. Pathogenic computational verdict because pathogenic predictions from DANN, EIGEN, FATHMM-MKL, M-CAP, MutationAssessor, MutationTaster, PrimateAI, REVEL and SIFT. We interpret it as variant of uncertain significance (VUS). ACMG/AMP criteria applied: PP3.