Submissions for variant NM_003901.4(SGPL1):c.766A>G (p.Ile256Val)

gnomAD frequency: 0.00010  dbSNP: rs759865429

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001987596	SCV002223363	uncertain significance	not provided	2024-10-16	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 256 of the SGPL1 protein (p.Ile256Val). This variant is present in population databases (rs759865429, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with SGPL1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1443563). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt SGPL1 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.
Genetic Services Laboratory, University of Chicago	RCV003151370	SCV003840040	uncertain significance	not specified	2022-12-16	no assertion criteria provided	clinical testing	DNA sequence analysis of the SGPL1 gene demonstrated a sequence change, c.766A>G, in exon 9 that results in an amino acid change, p.Ile256Val. This sequence change does not appear to have been previously described in individuals with SGPL1-related disorders. This sequence change has been described in the gnomAD database with a frequency of 0.018% in the European subpopulation (dbSNP rs759865429). The p.Ile256Val change affects a moderately conserved amino acid residue located in a domain of the SGPL1 protein that is known to be functional. The p.Ile256Val substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Ile256Val change remains unknown at this time. Biallelic pathogenic variants in SGPL1 are associated with nephrotic syndrome, type 14 [OMIM# 617575] a recessive form of steroid-resistant nephrotic syndrome with multisystemic manifestations. Some affected males have been reported with micropenis, cryptorchidism, and absent testes.