Submissions for variant NM_022367.4(SEMA4A):c.1301T>C (p.Met434Thr)

gnomAD frequency: 0.00044  dbSNP: rs146822426

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000082098	SCV000114044	uncertain significance	not provided	2015-03-04	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000082098	SCV001222771	uncertain significance	not provided	2025-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 434 of the SEMA4A protein (p.Met434Thr). This variant is present in population databases (rs146822426, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with SEMA4A-related conditions. ClinVar contains an entry for this variant (Variation ID: 96033). 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 expected to disrupt SEMA4A protein function with a positive 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.
Illumina Laboratory Services, Illumina	RCV001095829	SCV001252005	likely benign	Retinitis pigmentosa	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina	RCV001095830	SCV001252006	uncertain significance	Cone-rod dystrophy 10	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004815016	SCV005070773	uncertain significance	Optic atrophy	2022-01-01	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004815015	SCV005073497	uncertain significance	Retinal dystrophy	2022-01-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000082098	SCV005889876	uncertain significance	not provided	2025-01-01	criteria provided, single submitter	clinical testing
CSER _CC_NCGL, University of Washington	RCV000417364	SCV000503548	uncertain significance	Colorectal cancer	2016-08-01	no assertion criteria provided	research	This gene does not have an established association with colon cancer risk. Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 76 year old with pancreatic cancer diagnosed at age 64, colon cancer diagnosed at age 72 and a history of over 20 colon polyps. Family history is positive for colon cancer in a paternal uncle diagnosed in his 70s.