Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001175608 | SCV001339261 | uncertain significance | not specified | 2020-03-03 | criteria provided, single submitter | clinical testing | Variant summary: SPRED1 c.353G>A (p.Arg118Lys) results in a conservative amino acid change located in the WH1/EVH1 domain (IPR000697) and SPRE, EVH1 domain (IPR041937) 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 8e-06 in 250964 control chromosomes (gnomAD v2). Furthermore, the variant allele was found at a frequency of 0.00006983 in 143200 control chromosomes, predominantly at a frequency of 0.0002381 (10 individuals) within the African or African-American subpopulation in the gnomAD (v3) database. This variant frequency is approximately 95 fold of the estimated maximal expected allele frequency for a pathogenic variant in SPRED1 causing Noonan Syndrome and Related Conditions phenotype (2.5e-06), suggesting the variant may be a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.353G>A in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. |
| Invitae | RCV001875779 | SCV002250108 | uncertain significance | Legius syndrome | 2022-05-03 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 118 of the SPRED1 protein (p.Arg118Lys). This variant is present in population databases (rs373381933, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with SPRED1-related conditions. ClinVar contains an entry for this variant (Variation ID: 918167). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Ambry Genetics | RCV002451355 | SCV002613653 | uncertain significance | Cardiovascular phenotype | 2021-07-08 | criteria provided, single submitter | clinical testing | The p.R118K variant (also known as c.353G>A), located in coding exon 3 of the SPRED1 gene, results from a G to A substitution at nucleotide position 353. The arginine at codon 118 is replaced by lysine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |