Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Genomic Research Center, |
RCV000714860 | SCV000845604 | uncertain significance | Otitis media, susceptibility to | 2018-08-07 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV001303988 | SCV001493255 | uncertain significance | not provided | 2025-01-19 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Arg893*) in the A2ML1 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in A2ML1 cause disease. This variant is present in population databases (rs199651558, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with otitis-prone (PMID: 26121085). ClinVar contains an entry for this variant (Variation ID: 217310). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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, |
RCV002307443 | SCV002600863 | likely benign | not specified | 2022-10-31 | criteria provided, single submitter | clinical testing | Variant summary: A2ML1 c.2677C>T (p.Arg893X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are not commonly known mechanisms for Noonan Syndrome and Related Conditions in the A2ML1 gene. Truncations in A2ML1 have been classified as benign by our laboratory for Noonan Syndrome and Related Conditions (e.g. c.1444_1445delAG (p.Ser482ProfsX2), c.3676_3677delGC (p.Ala1226GlnfsX34), c.4261C>T (p.Gln1421X)). The variant allele was found at a frequency of 0.00012 in 278180 control chromosomes (gnomAD). The observed variant frequency is approximately 30-fold of the estimated maximal expected allele frequency for a pathogenic variant in A2ML1 causing Noonan Syndrome phenotype (4e-06), suggesting that the variant is benign. The variant, c.2677C>T, has been reported in the literature in individuals affected with otitis media and hypertension (Santos-Cortez_2015, Surendran_2016), however, to our knowledge, no occurrence in individuals affected with Noonan Syndrome has been reported and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both classified the variant as uncertain significance. Based on the evidence outlined above, although the variant might be associated with an elevated risk for otitis media (or other disease phenotypes), however it is unlikely to be associated with Noonan Syndrome, therefore the variant was classified as likely benign. |
| Department of Molecular and Human Genetics, |
RCV000201249 | SCV000255636 | uncertain significance | Nonsyndromic otitis media | 2014-05-28 | no assertion criteria provided | research |