Submissions for variant NM_006080.3(SEMA3A):c.1546C>T (p.Arg516Trp)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002988170	SCV003715389	uncertain significance	Inborn genetic diseases	2021-12-06	criteria provided, single submitter	clinical testing	The c.1546C>T (p.R516W) alteration is located in exon 14 (coding exon 14) of the SEMA3A gene. This alteration results from a C to T substitution at nucleotide position 1546, causing the arginine (R) at amino acid position 516 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003575021	SCV004344165	uncertain significance	not provided	2023-01-19	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with SEMA3A-related conditions. This variant is present in population databases (rs148900275, gnomAD 0.02%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 516 of the SEMA3A protein (p.Arg516Trp). 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 SEMA3A protein function. 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004587457	SCV005076600	uncertain significance	not specified	2024-04-24	criteria provided, single submitter	clinical testing	Variant summary: SEMA3A c.1546C>T (p.Arg516Trp) results in a non-conservative amino acid change located in the PSI domain (IPR016201) 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 9.2e-05 in 250188 control chromosomes. c.1546C>T has been reported in the literature in at least one individual affected with normosmic hypogonadotropic hypogonadism (Federici_2022). 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 have been ascertained in the context of this evaluation (PMID: 36531499). ClinVar contains an entry for this variant (Variation ID: 2372573). Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003396866	SCV004120492	uncertain significance	SEMA3A-related disorder	2024-06-23	no assertion criteria provided	clinical testing	The SEMA3A c.1546C>T variant is predicted to result in the amino acid substitution p.Arg516Trp. This variant has been reported in the heterozygous state in an individual with primary lymphedema and inflammation of lymphatic vessels; however, it was also present in the healthy mother (Ricci et al. 2020. PubMed ID: 33190429). This variant is reported in 0.020% of alleles in individuals of African descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.