Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000490108 | SCV000577816 | likely pathogenic | not provided | 2015-04-28 | criteria provided, single submitter | clinical testing | The W1186S variant in the LRP4 gene has been reported previously as a de novo heterozygous mutation in an individual with sclerosteosis, syndactyly, and shortening of several phalanges (Leupin et al., 2011). Functional studies demonstrated that W1186S impairs sclerostin interaction with LRP4 and sclerostin facilitator function (Leupin et al., 2011). The W1186S variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The W1186S variant is a non-conservative amino acid substitution which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts that this variant is probably damaging to the protein structure/function. The W1186S variant is a strong candidate for a disease-causing variant, however the possibility that it may be a rare benign variant cannot be excluded. |
| Invitae | RCV000800068 | SCV000939767 | uncertain significance | Cenani-Lenz syndactyly syndrome; Sclerosteosis 2; Congenital myasthenic syndrome 17 | 2018-09-11 | criteria provided, single submitter | clinical testing | This sequence change replaces tryptophan with serine at codon 1186 of the LRP4 protein (p.Trp1186Ser). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with sclerosteosis (PMID: 21471202). ClinVar contains an entry for this variant (Variation ID: 30410). Experimental studies have shown that this missense change impairs LRP4 protein function in vitro (PMID: 21471202, 24234652). 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. |
| OMIM | RCV000023363 | SCV000044654 | pathogenic | Sclerosteosis 2 | 2014-04-01 | no assertion criteria provided | literature only |