Submissions for variant NM_152594.3(SPRED1):c.26A>T (p.Asp9Val)

gnomAD frequency: 0.00010  dbSNP: rs200157475

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041240	SCV000064931	benign	not specified	2018-05-25	criteria provided, single submitter	clinical testing	p.Asp9Val in exon 1 of SPRED1: This variant is classified as benign because it h as been identified in 0.5% (49/9150) of Ashkenazi Jewish chromosomes by the Geno me Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs20015 7475). ACMG/AMP criteria applied: BA1.
GeneDx	RCV000680360	SCV000530149	likely benign	not provided	2019-10-11	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26635368, 22753041, 31401120)
Invitae	RCV001082112	SCV000645821	benign	Legius syndrome	2024-01-29	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000680360	SCV001149385	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	SPRED1: BS1
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000041240	SCV001338222	benign	not specified	2020-02-24	criteria provided, single submitter	clinical testing	Variant summary: SPRED1 c.26A>T (p.Asp9Val) results in a non-conservative amino acid change located in the WH1/EVH1 domain (IPR000697) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00068 in 195612 control chromosomes, predominantly at a frequency of 0.0025 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 1000 fold of the estimated maximal expected allele frequency for a pathogenic variant in SPRED1 causing Noonan Syndrome and Related Conditions phenotype (2.5e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrence with another pathogenic variant has been internally reported (PTPN11 c.172A>T, p.Asn58Tyr), providing supporting evidence for a benign role. Four ClinVar submitters (evaluation after 2014) cites the variant as uncertain significance (1x), likely benign (1x) and benign (2x). Based on the evidence outlined above, the variant was classified as benign.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813368	SCV002060693	benign	Noonan syndrome and Noonan-related syndrome	2019-10-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002453336	SCV002739949	benign	Cardiovascular phenotype	2021-11-01	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.
PreventionGenetics, part of Exact Sciences	RCV003944953	SCV004770781	likely benign	SPRED1-related condition	2022-05-16	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).