Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000415388 | SCV000823235 | pathogenic | Legius syndrome | 2024-11-07 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Arg325*) in the SPRED1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 120 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, 25883013; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 374301). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects SPRED1 function (PMID: 17704776). This variant disrupts a region of the SPRED1 protein in which other variant(s) (p.Gly385Ilefs*20, p.Arg349Glyfs*11) have been determined to be pathogenic (PMID: 17704776, 21089071, 21649642). 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. |
| Ambry Genetics | RCV002379279 | SCV002695329 | pathogenic | Cardiovascular phenotype | 2017-05-05 | criteria provided, single submitter | clinical testing | The p.R325* pathogenic mutation (also known as c.973C>T), located in coding exon 7 of the SPRED1 gene, results from a C to T substitution at nucleotide position 973. This changes the amino acid from an arginine to a stop codon within coding exon 7. This mutation was originally identified in a patient with neurofibromatosis 1 (NF1)-like phenotype (Brems H et al. Nat. Genet., 2007 Sep;39:1120-6) and subsequently reported in multiple patients with NF1 features (Messiaen L et al. JAMA, 2009 Nov;302:2111-8; Benelli E et al. Ital J Pediatr, 2015 Feb;41:8). In addition, this mutation results in loss of the Sprouty domain, and R325* mutant protein lacked the ability to negatively regulate the Ras-MAPK pathway (Brems H et al. Nat. Genet., 2007 Sep;39:1120-6). This alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation. |
| Laan Lab, |
RCV003991577 | SCV004231719 | pathogenic | Male infertility with spermatogenesis disorder | 2023-12-01 | criteria provided, single submitter | research | In addition, the same case carried one additional variant: TP63 c.1283C>T p.P428L, indicating a digenic effect. |
| Baylor Genetics | RCV000415388 | SCV000328775 | pathogenic | Legius syndrome | 2015-04-10 | no assertion criteria provided | clinical testing | This de novo pathogenic variant has been previously reported as disease-causing [PMID 17704776] and was found in our laboratory in a 6 month old female with delayed motor milestones, generalized hypotonia with tracheostomy, micrognathia, camptodactyly and overriding toes, failure to thrive, patent foramen ovale, and hemangioma on the left hand. A homozygous pathogenic variant in MEGF10 (NM_032446.2, c.1557delA) was reported in the same individual. |