Submissions for variant NM_001080442.3(SLC38A8):c.269G>T (p.Gly90Val)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV003154457	SCV003842693	uncertain significance	not provided	2022-09-13	criteria provided, single submitter	clinical testing	Observed with a pathogenic variant in a patient with foveal hypoplasia in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Ehrenberg et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33594928)
Labcorp Genetics (formerly Invitae), Labcorp	RCV003154457	SCV004330971	uncertain significance	not provided	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 90 of the SLC38A8 protein (p.Gly90Val). This variant is present in population databases (rs768657069, gnomAD 0.1%). This missense change has been observed in individual(s) with autosomal recessive foveal hypoplasia (PMID: 33594928; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 2444709). 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 not expected to disrupt SLC38A8 protein function with a negative predictive value of 80%. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004783044	SCV005395292	uncertain significance	not specified	2024-09-20	criteria provided, single submitter	clinical testing	Variant summary: SLC38A8 c.269G>T (p.Gly90Val) results in a non-conservative amino acid change located in the Amino acid transporter, transmembrane domain (IPR013057) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 250342 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in SLC38A8 causing Foveal Hypoplasia, Optic Nerve Decussation Defect, Anterior Segment Dysgenesis Syndrome, allowing no conclusion about variant significance. c.269G>T has been reported in the literature in an individual affected with Infantile nystagmus with foveal hypoplasia (Ehrenberg_2021). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 33594928). ClinVar contains an entry for this variant (Variation ID: 2444709). Based on the evidence outlined above, the variant was classified as uncertain significance.