Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000755968 | SCV000249831 | uncertain significance | not provided | 2023-06-12 | criteria provided, single submitter | clinical testing | Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22696272) |
| Ambry Genetics | RCV002315547 | SCV000738607 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection | 2016-05-25 | criteria provided, single submitter | clinical testing | The p.G1414S variant (also known as c.4240G>A), located in coding exon 55 of the COL5A1 gene, results from a G to A substitution at nucleotide position 4240. The glycine at codon 1414 is replaced by serine, an amino acid with similar properties. Internal structural analysis indicates that this alteration disrupts the characteristic G-X-Y motif of the triple helical domain in the COL5A1 protein and inserts a bulky side chain into a sterically-constrained region (Bella J et al. Science. 1994;266:75-81; Hohenester E et al. Proc. Natl. Acad. Sci. U.S.A. 2008;105:18273-7; Ambry internal data). Glycine substitutions in the triple helical domain of COL5A1 have been reported in association with classic Ehlers-Danlos syndrome (cEDS), but the number of affected individuals is limited and several COL5A1 glycine substitutions in the triple helical domain (e.g., p.G1078A and p.G1414A) are too common for disease in population databases (Symoens S et al. Hum. Mutat., 2012 Oct;33:1485-93; Ritelli M et al. Orphanet J Rare Dis. 2013 Apr;8:58). Based on data from gnomAD, this alteration has a frequency of 0.1% (10/9680) in the Ashkenazi Jewish subpopulation, which is higher than expected for disease, but as this is a founder population, the possibility that this alteration represents a founder mutation cannot be eliminated. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be probably damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Center for Human Genetics, |
RCV000659460 | SCV000781275 | uncertain significance | Ehlers-Danlos syndrome, classic type | 2016-11-01 | criteria provided, single submitter | clinical testing | |
| ARUP Laboratories, |
RCV000755968 | SCV000883657 | uncertain significance | not provided | 2018-03-04 | criteria provided, single submitter | clinical testing | The COL5A1 c.4240G>A; p.Gly1414Ser variant (rs776709663; ClinVar variant ID 212974), to our knowledge, is not reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.006% (identified on 15 out of 233,700 chromosomes) and an Ashkenazi Jewish population frequency of 0.12% (identified on 12 out of 9,500 chromosomes). The glycine at position 1414 is highly conserved, considering 12 species, and is located in a conserved Gly-X-Y repeat. Changes to glycine residues in Gly-X-Y motifs in triple helix domains disrupt helix formation and are predicted to be deleterious (Weerakkody 2016); however, the allele frequency in the Ashkenazi Jewish population indicates this may be a tolerated polymorphic change. Based on the available information, the clinical significance of the p.Gly1414Ser variant cannot be determined with certainty. |
| Invitae | RCV003114350 | SCV003786242 | benign | Ehlers-Danlos syndrome, classic type, 1 | 2023-10-23 | criteria provided, single submitter | clinical testing |