Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000542730 | SCV000652063 | pathogenic | Cutis laxa, autosomal recessive, type 1B | 2023-09-08 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 472824). This missense change has been observed in individual(s) with clinical features of thoracic aortic aneurysms and dissections (PMID: 28673110; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (no rsID available, gnomAD 0.07%). This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 137 of the EFEMP2 protein (p.Ser137Cys). For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on EFEMP2 protein function. |
| Ambry Genetics | RCV002324035 | SCV002626815 | likely pathogenic | Cardiovascular phenotype | 2022-05-11 | criteria provided, single submitter | clinical testing | The p.S137C variant (also known as c.409A>T), located in coding exon 4 of the EFEMP2 gene, results from an A to T substitution at nucleotide position 409. The serine at codon 137 is replaced by cysteine, an amino acid with dissimilar properties. This variant was detected as homozygous in a child with cutis laxa and significant aneurysmal aortic dilation (Yetman AT et al. World J Pediatr Congenit Heart Surg, 2019 05;10:376-379; Thomas P et al. Front Cardiovasc Med, 2021 Nov;8:756765). This variant has also been reported in additional homozygous and compound heterozygous cases with severe aortic dilation, often with early ages of onset (Ambry internal data; Invitae pers. comm.). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Fulgent Genetics, |
RCV000542730 | SCV002777676 | uncertain significance | Cutis laxa, autosomal recessive, type 1B | 2021-10-08 | criteria provided, single submitter | clinical testing |