Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000798908 | SCV000938551 | uncertain significance | not provided | 2024-01-13 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 799 of the A2ML1 protein (p.Ser799Ala). This variant is present in population databases (rs374408168, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with A2ML1-related conditions. ClinVar contains an entry for this variant (Variation ID: 644912). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001175521 | SCV001339129 | likely benign | not specified | 2020-03-23 | criteria provided, single submitter | clinical testing | Variant summary: A2ML1 c.2395T>G (p.Ser799Ala) results in a conservative amino acid change located in the Alpha-2-macroglobulin domain of the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 249568 control chromosomes, predominantly at a frequency of 0.0009 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is significantly above the estimated maximal expected allele frequency for a pathogenic variant in A2ML1 causing Noonan Syndrome phenotype (4e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.2395T>G in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. |
| Ambry Genetics | RCV002458447 | SCV002738473 | uncertain significance | Inborn genetic diseases | 2023-06-29 | criteria provided, single submitter | clinical testing | The p.S799A variant (also known as c.2395T>G), located in coding exon 19 of the A2ML1 gene, results from a T to G substitution at nucleotide position 2395. The serine at codon 799 is replaced by alanine, an amino acid with 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. |