Submissions for variant NM_152594.3(SPRED1):c.939G>A (p.Thr313=)

gnomAD frequency: 0.00070  dbSNP: rs140644874

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001079971	SCV000291526	benign	Legius syndrome	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000588514	SCV000520807	likely benign	not provided	2020-07-31	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 28150585)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588514	SCV000699964	benign	not provided	2017-04-18	criteria provided, single submitter	clinical testing	Variant summary: The SPRED1 c.939G>A (p.Thr313Thr) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect binding of multiple ESE sites. However, no functional studies are available to confirm these predictions. This variant was found in 78/121206 control chromosomes from ExAC at a frequency of 0.0006435, which is approximately 257 times the estimated maximal expected allele frequency of a pathogenic SPRED1 variant (0.0000025), therefore this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as benign. Taken together, this variant is classified as Benign.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000434497	SCV000710934	benign	not specified	2017-11-14	criteria provided, single submitter	clinical testing	p.Thr313Thr in exon 7 of SPRED1: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue, is not located with in the splice consensus sequence, and has been identified in 0.1% (35/25780) of African American chromosomes by the Genome Aggregation Database (gnomAD, http:// gnomad.broadinstitute.org; dbSNP rs140644874).
Illumina Laboratory Services, Illumina	RCV001079971	SCV001274828	likely benign	Legius syndrome	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.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813436	SCV002060703	benign	Noonan syndrome and Noonan-related syndrome	2019-11-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000588514	SCV002063409	likely benign	not provided	2024-04-01	criteria provided, single submitter	clinical testing	SPRED1: BP4, BP7
Ambry Genetics	RCV002374382	SCV002683752	likely benign	Cardiovascular phenotype	2022-04-09	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Clinical Genetics, Academic Medical Center	RCV000434497	SCV001923398	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000588514	SCV001955794	likely benign	not provided		no assertion criteria provided	clinical testing