Submissions for variant NM_000295.5(SERPINA1):c.922G>T (p.Ala308Ser)

gnomAD frequency: 0.00222  dbSNP: rs141620200

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000366637	SCV000342565	benign	not specified	2016-06-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000766819	SCV000565551	uncertain significance	not provided	2024-08-09	criteria provided, single submitter	clinical testing	Reported in an individual with features of alpha-1-antitrypsin deficiency who was also homozygous for the Z allele, which explained the phenotype (Per Bengtson et al. Phenotyping of a-1-Antitrypsin by liquid chromatographyhigh resolution mass spectrometry. Clinical Mass Spectrometry. 2016); Identified in large case control studies in several individuals with lung disease who also harbored the Z variant, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes, and at least one of the individuals had normal serum concentrations of AAT (PMID: 31661293, 30254761); Reported in one individual with chronic respiratory disorder in whom no second SERPINA1 variant was identified (PMID: 26987331); In a large study evaluating the rates of venous thromboembolism (VTE), the allele frequency of this variant was found to be 0.4% higher in individuals who had experienced VTE; the variant was seen in the homozygous state in at least one individual with VTE and in the compound heterozygous state in individuals with and without VTE, but detailed clinical information, including AAT serum levels, was not provided (PMID: 35263815); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30223862, 25010111, 32810967, 30254761, 35263815, 26987331, 31661293, 38637533, 36367950)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001081168	SCV000754980	likely benign	Alpha-1-antitrypsin deficiency	2024-01-31	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000366637	SCV000966516	likely benign	not specified	2013-02-21	criteria provided, single submitter	clinical testing	Ala308Ser in exon 6 of SERPINA1: This variant is not expected to have clinical s ignificance because it has been identified in 0.4% (33/8600) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs141620200).
Illumina Laboratory Services, Illumina	RCV001081168	SCV001279506	uncertain significance	Alpha-1-antitrypsin deficiency	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
PreventionGenetics, part of Exact Sciences	RCV003401263	SCV004110652	uncertain significance	SERPINA1-related disorder	2023-06-02	criteria provided, single submitter	clinical testing	The SERPINA1 c.922G>T variant is predicted to result in the amino acid substitution p.Ala308Ser. This variant has been reported as a variant of uncertain significance in trans with the common SERPINA1 Z allele as well as the F allele in patients with chronic obstructive pulmonary disease (COPD) (Foil et al. 2018. PubMed ID: 30254761; Ortega et al. 2020. PubMed ID: 31661293). This variant is reported in 0.39% of alleles in individuals of European (Non-Finnish) descent in gnomAD, including one homozygous individual (http://gnomad.broadinstitute.org/variant/14-94845944-C-A). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
CeGaT Center for Human Genetics Tuebingen	RCV000766819	SCV004130296	likely benign	not provided	2023-06-01	criteria provided, single submitter	clinical testing	SERPINA1: BS2