Submissions for variant NM_001127701.1(SERPINA1):c.1178C>T (p.Pro393Leu)

gnomAD frequency: 0.00011  dbSNP: rs199422209

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000409001	SCV000486942	likely pathogenic	Alpha-1-antitrypsin deficiency	2016-09-09	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000727230	SCV000706787	pathogenic	not provided	2017-03-14	criteria provided, single submitter	clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000409001	SCV001449018	pathogenic	Alpha-1-antitrypsin deficiency	2019-07-03	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000409001	SCV001591259	pathogenic	Alpha-1-antitrypsin deficiency	2023-11-07	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 393 of the SERPINA1 protein (p.Pro393Leu). This variant is present in population databases (rs199422209, gnomAD 0.01%). This missense change has been observed in individuals with autosomal recessive alpha-1-antitrypsin deficiency (AATD) (PMID: 2784123, 10234508, 18024524). This variant is also known as MHerleen and as Pro369Leu. ClinVar contains an entry for this variant (Variation ID: 17965). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SERPINA1 function (PMID: 10234508). This variant disrupts the p.Pro393 amino acid residue in SERPINA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10234508, 18024524, 27296815). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002336088	SCV002638503	pathogenic	Inborn genetic diseases	2017-06-14	criteria provided, single submitter	clinical testing	The p.P393L pathogenic mutation (also known as c.1178C>T), located in coding exon 4 of the SERPINA1 gene, results from a C to T substitution at nucleotide position 1178. The proline at codon 393 is replaced by leucine, an amino acid with similar properties. This mutation comprises the deficiency allele PI*Mheerlen. The resulting mutant protein is not secreted but is retained in the endoplasmic reticulum (Poller W et al. Eur. J. Hum. Genet., 1999 Apr;7:321-31). This mutation was identified in an individual in trans with a null allele with severe chronic obstructive pulmonary disease and extremely low serum alpha-1-antitrypsin levels (Poller W et al. Eur. J. Hum. Genet., 1999 Apr;7:321-31). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Fulgent Genetics, Fulgent Genetics	RCV000409001	SCV002810316	pathogenic	Alpha-1-antitrypsin deficiency	2022-03-08	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000409001	SCV004203120	pathogenic	Alpha-1-antitrypsin deficiency	2024-03-19	criteria provided, single submitter	clinical testing
OMIM	RCV000019565	SCV000039862	other	PI M(HEERLEN)	2016-07-20	no assertion criteria provided	literature only
GeneReviews	RCV000409001	SCV000256621	pathogenic	Alpha-1-antitrypsin deficiency	2014-05-01	no assertion criteria provided	literature only
Department of Laboratory Medicine and Genetics, Trillium Health Partners Credit Valley Hospital	RCV000409001	SCV000608300	pathogenic	Alpha-1-antitrypsin deficiency	2014-12-08	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000727230	SCV001739769	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000727230	SCV001809663	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000727230	SCV001968697	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003944831	SCV004766713	pathogenic	SERPINA1-related disorder	2024-07-15	no assertion criteria provided	clinical testing	The SERPINA1 c.1178C>T variant is predicted to result in the amino acid substitution p.Pro393Leu. This variant has been reported in multiple individuals with alpha-1-antitrypsin deficiency and has been referred to as the PI MHeerlen allele (Hofker et al. 1989. PubMed ID: 2784123; Poller et al. 1999. PubMed ID: 10234508; Giacopuzzi et al. 2018. PubMed ID: 29882371). Functional studies found this variant results in retention of the protein in the endoplasmic reticulum (Poller et al. 1999. PubMed ID: 10234508). This variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.