Submissions for variant NM_152594.3(SPRED1):c.1149_1152del (p.Gly385fs)

dbSNP: rs1595763925

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000801189	SCV000940955	pathogenic	Legius syndrome	2023-07-14	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly385Ilefs*20) in the SPRED1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 60 amino acid(s) of the SPRED1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Legius syndrome (PMID: 17704776, 21089071). ClinVar contains an entry for this variant (Variation ID: 646826). This variant disrupts a region of the SPRED1 protein in which other variant(s) (p.Phe400Valfs*32, p.Cys418Alafs*6, p.Met417Ttrfs*15, p.Arg403Leufs*30) have been determined to be pathogenic (PMID: 19920235; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Mendelics	RCV000801189	SCV001139543	pathogenic	Legius syndrome	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001090730	SCV001246419	pathogenic	not provided	2018-12-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001090730	SCV002546753	likely pathogenic	not provided	2024-09-17	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in abnormal protein length as the last 60 amino acid(s) are replaced with 19 different amino acid(s), and other similar variants have been reported in HGMD; Identified in patients with multiple cafe-au-lait macules with or without axillary/inguinal freckling referred for genetic testing at GeneDx and in published literature (PMID: 17704776, 21089071, 19920235); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17704776, 21089071, 21548021, 19920235)
Ambry Genetics	RCV002458462	SCV002617563	pathogenic	Cardiovascular phenotype	2016-12-06	criteria provided, single submitter	clinical testing	The c.1149_1152delAGAG pathogenic mutation, located in coding exon 7 of the SPRED1 gene, results from a deletion of 4 nucleotides at positions 1149 to 1152, causing a translational frameshift with a predicted alternate stop codon (p.G385Ifs*20). This frameshift occurs at the 3' terminus of SPRED1 and impacts the last 60 amino acids of the protein, including the functionally important Sprouty-related domain. This deletion was originally identified in a patient with café-au-lait spots and mild freckling (Brems H et al. Nat. Genet., 2007 Sep;39:1120-6). Subsequently, the same mutation has been reported in multiple patients with clinical features of Legius syndrome (Messiaen L et al. JAMA, 2009 Nov;302:2111-8; Denayer E et al. Hum. Mutat., 2011 Jan;32:E1985-98; Spencer E et al. Am. J. Med. Genet. A, 2011 Jun;155A:1352-9). In addition to the clinical data presented in the literature, this mutation is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000801189	SCV005091026	pathogenic	Legius syndrome	2023-10-02	criteria provided, single submitter	clinical testing	PVS1, PM2, PP5 - ClinVar contains an entry for this variant (Variation ID: 646826). Low frequency in gnomAD population databases. Loss-of-function variants in SPED1 are known to be pathogenic (PMID: 21548021).