Submissions for variant NM_000062.3(SERPING1):c.1070T>A (p.Ile357Asn)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003557603	SCV004294841	uncertain significance	not provided	2023-11-04	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 357 of the SERPING1 protein (p.Ile357Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with angioedema (PMID: 18586324, 21864911). This variant is also known as Ile335Asn. 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 SERPING1 protein function with a positive predictive value of 80%. This variant disrupts the p.Ile357 amino acid residue in SERPING1. Other variant(s) that disrupt this residue have been observed in individuals with SERPING1-related conditions (PMID: 31517426), which suggests that this may be a clinically significant amino acid residue. 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.
DNA-diagnostics Laboratory, Research Centre For Medical Genetics	RCV004579618	SCV005061767	pathogenic	Hereditary angioedema type 1	2024-06-01	criteria provided, single submitter	research	The pathogenic or likely pathogenic SERPING1 gene variants are detected in >90% of the HAE1/2 families and in >80% of the total HAE families (e.g., DOI: 10.1016/j.molimm.2008.05.007, 10.1159/2F000138883, 10.1016/j.molimm.2011.07.010). In our study, the heterozygous c.1070T>A (p.Ile357Asn) variant in SERPING1 was observed in 1 HAE1 family case. The same variant has previously been reported in 1 HAE1 family case (DOI: 10.1016/j.molimm.2008.05.007). Extensive and comparative in vitro studies of 6 functional parameters, including secretion potential, intra-cellular solubility, protease complex formation, and trans-acting impact on normal C1INH have indicated that the c.1070T>A variant exhibits a dominant-negative variant like behavior and characterized by low secretion, but with the capacity to change the intracellular distribution of normal C1INH protein (increasing its presence in the insoluble fraction) without inducing detectable formation of C1INH foci. (DOI: 10.1016/j.jaci.2023.04.023). Such in silico algorithms as BayesDel, MutPred, REVEL support a deleterious effect of the c.1070T>A variant with Moderate evidence of pathogenicity, when choosing at least two identical assessments and using the threshold ranges from ClinGen recommendations (DOI: 10.1016/j.ajhg.2022.10.013). In summary, the c.1070T>A variant in SERPING1 meets ACMG/ClinGen SVI guidance criteria to be classified as pathogenic: PP4_Str, PS3_Mod, PP3_Mod, PS4_Sup, PM2_Sup, PP2