Submissions for variant NM_012431.3(SEMA3E):c.1991C>T (p.Thr664Met) (rs375536813)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000998823	SCV001155110	uncertain significance	not provided	2018-05-01	criteria provided, single submitter	clinical testing
Invitae	RCV001053945	SCV001218232	uncertain significance	CHARGE association	2019-12-06	criteria provided, single submitter	clinical testing	This sequence change replaces threonine with methionine at codon 664 of the SEMA3E protein (p.Thr664Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs375536813, ExAC 0.01%). This variant has not been reported in the literature in individuals with SEMA3E-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Department of Pathology and Laboratory Medicine,Sinai Health System	RCV000998823	SCV001551413	uncertain significance	not provided		no assertion criteria provided	clinical testing	The SEMA3E p.Thr604Met variant was not identified in the literature nor was it identified in the ClinVar, Cosmic or MutDB databases. The variant was identified in dbSNP (ID: rs375536813) and LOVD 3.0. The variant was identified in control databases in 1 of 249208 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following population: European (non-Finnish) in 1 of 112562 chromosomes (freq: 0.000009), while the variant was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other, and South Asian populations. The p.Thr604 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, BLOSUM, and MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.