Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV001011589 | SCV001171927 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2019-04-16 | criteria provided, single submitter | clinical testing | The p.L48P variant (also known as c.143T>C), located in coding exon 1 of the MEN1 gene, results from a T to C substitution at nucleotide position 143. The leucine at codon 48 is replaced by proline, an amino acid with similar properties. This alteration has been detected an in individual with a clinical history consistent with MEN1 (Ambry internal data). Based on internal structural analysis, this variant is more disruptive than known pathogenic variants (Ambry internal data). This alteration has not been reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly 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. |
Invitae | RCV001860673 | SCV002193293 | uncertain significance | Multiple endocrine neoplasia, type 1 | 2021-02-11 | criteria provided, single submitter | clinical testing | This variant has been observed in individual(s) with clinical features of multiple endocrine neoplasia type 1 (MEN1) (PMID: 30339208, 30869828). ClinVar contains an entry for this variant (Variation ID: 819220). 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. 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) performed at Invitae indicates that this missense variant is expected to disrupt MEN1 protein function. This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 48 of the MEN1 protein (p.Leu48Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. |