Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000423987 | SCV000514608 | pathogenic | not provided | 2023-02-27 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate a damaging effect; N291H reduces secretion of the wild-type protein by a dominant negative mechanism (Haslund et al., 2019); Not observed in large population cohorts (gnomAD); 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: 18758157, 31517426, 29753808, 25258140, 30398465) |
Department of Immunology and Histocompatibility, |
RCV000768684 | SCV000900054 | likely pathogenic | Hereditary angioedema type 1 | criteria provided, single submitter | clinical testing | The c.871A>C (p.Asn291His) variant has been previously reported in association with hereditary angioedema in the literature (Gosswein et al., 2008; Loules et al., 2018), in HAE database (http://hae.enzim.hu/detail.php?id=43) and in ClinVar database. The variant has not been detected in approximately 120000 individuals of the Exome Aggregation Consortium (ExAC) database, indicating that it is not a common variant. It was detected by our laboratory in 1 Greek male patient with C1-INH-HAE Type I. The mutation was not detected in a healthy family member that was also tested (patient's sister). A missense variant changing the same residue (p.Asn291Tyr) has been previously reported in association with angioedema. Taking all the above into account and according to ACMG Guidelines (Criteria: PM2, PM6, PP2, PP4, PP5) the variant is considered likely pathogenic. | |
Labcorp Genetics |
RCV000423987 | SCV004294836 | uncertain significance | not provided | 2023-06-29 | criteria provided, single submitter | clinical testing | 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. Experimental studies have shown that this missense change affects SERPING1 function (PMID: 30398465). 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 SERPING1 protein function. ClinVar contains an entry for this variant (Variation ID: 378573). This missense change has been observed in individual(s) with hereditary angioedema (PMID: 18758157). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 291 of the SERPING1 protein (p.Asn291His). |