Submissions for variant NM_152594.3(SPRED1):c.291G>A (p.Lys97=)

gnomAD frequency: 0.82029  dbSNP: rs7182445

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000041241	SCV000058320	benign	not specified	2015-09-10	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041241	SCV000064932	benign	not specified	2012-03-14	criteria provided, single submitter	clinical testing	Lys97Lys in exon 3 of SPRED1: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and it has been identified in 90% (6302/7020) of European American chromosomes and 69% (2576/3738) of African American chromosome s from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.w ashington.edu/EVS/; dbSNP rs7182445).
PreventionGenetics, part of Exact Sciences	RCV000041241	SCV000316209	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000034273	SCV000390787	benign	Legius syndrome	2018-01-12	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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034273	SCV000605256	benign	Legius syndrome	2023-11-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588250	SCV000699958	benign	not provided	2017-04-17	criteria provided, single submitter	clinical testing	Variant summary: The SPRED1 c.291G>A (p.Lys97Lys) variant involves the alteration of a conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts loss of the SRp40 and SF2/ASF binding motifs. However, these predictions have yet to be confirmed by functional studies. The variant of interest has been found in a large, broad control population, ExAC in 104831/121368 control chromosomes (45684 homozygotes) at a frequency of 0.863745, which is approximately 345498 times the estimated maximal expected allele frequency of a pathogenic SPRED1 variant (0.0000025), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign.
Invitae	RCV000034273	SCV001000160	benign	Legius syndrome	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000588250	SCV001828429	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000034273	SCV002057649	benign	Legius syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002433491	SCV002751027	benign	Cardiovascular phenotype	2016-04-04	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000034273	SCV004015547	benign	Legius syndrome	2023-07-07	criteria provided, single submitter	clinical testing
GeneReviews	RCV000034273	SCV000058213	not provided	Legius syndrome		no assertion provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000034273	SCV000733436	benign	Legius syndrome		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000041241	SCV001920099	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000041241	SCV001953894	benign	not specified		no assertion criteria provided	clinical testing