Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM5PP3_StrongPP5_Moderate
The NM_000295(SERPINA1):c.1096G>C(p.Glu366Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD Genomes project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E366K) has been classified as Pathogenic.
Verdict is Pathogenic. Variant got 10 ACMG points.
GnomAD3 genomesCov.: 33 GnomAD3 exomes AF: 0.0000278AC: 7AN: 251360Hom.: 0 AF XY: 0.0000294AC XY: 4AN XY: 135856 GnomAD4 exome AF: 0.00000479AC: 7AN: 1461882Hom.: 0 AF XY: 0.00000550AC XY: 4AN XY: 727244
Submissions by phenotype
|Likely pathogenic, criteria provided, single submitter||clinical testing||Invitae||May 27, 2022||This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 366 of the SERPINA1 protein (p.Glu366Gln). This variant is present in population databases (no rsID available, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with SERPINA1-related conditions. 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 SERPINA1 protein function. This variant disrupts the p.Glu366 amino acid residue in SERPINA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 3500183, 9569237, 19083091). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -|
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