Submissions for variant NM_001127701.1(SERPINA1):c.739C>T (p.Arg247Cys)

gnomAD frequency: 0.00211  dbSNP: rs28929470

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000151833	SCV000200306	uncertain significance	not specified	2013-10-11	criteria provided, single submitter	clinical testing	The Arg247Cys variant in SERPINA1, also called the F allele, has been identified in 0.4% (35/8600) of European American chromosomes from a large population by t he NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/). This vari ant has been reported to affect protein function (Cook 1996) and may contribute to disease when homozygous or when present with other SERPINA1 variants (Ringenb ach 2011). Computational analyses (biochemical amino acid properties, AlignGVGD, PolyPhen2, and SIFT) also support an impact to the protein though their accurac y is not known. In summary, additional information is needed to fully assess the clinical significance of this variant.
Ambry Genetics	RCV000622899	SCV000740917	uncertain significance	Inborn genetic diseases	2017-03-17	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000727618	SCV000854881	uncertain significance	not provided	2018-08-30	criteria provided, single submitter	clinical testing
Mendelics	RCV000148879	SCV001139505	uncertain significance	Alpha-1-antitrypsin deficiency	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000148879	SCV001279508	likely benign	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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
GeneDx	RCV000727618	SCV001795194	uncertain significance	not provided	2023-11-28	criteria provided, single submitter	clinical testing	Commonly referred to as the F variant or R223C by alternate nomenclature, and has been reported multiple times in association with normal serum AAT levels when present in the homozygous state and mildly reduced AAT levels when present with another disease-causing SERPINA1 variant (PMID: 2035534, 22078084, 25098359); Homozygosity for R247C may increase susceptibility to elastase-induced lung damage but not emphysema, whereas this variant can be of clinical consequence when in the compound heterozygous state with the Z allele (E366K) (PMID: 25098359); 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: 25525159, 18682522, 26987331, 24713750, 8912354, 25637381, 24082139, 27153395, 22078084, 2035534, 9041988, 15115878, 29882371, 26310624, 23632999, 6306478, Wang2022[Functional Study], 20301692, 31819391, 32181528, 31450843, 26647313, 31661293, 35477570, 37622442, 25098359)
MGZ Medical Genetics Center	RCV000148879	SCV002579104	likely pathogenic	Alpha-1-antitrypsin deficiency	2022-04-11	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000148879	SCV003525719	uncertain significance	Alpha-1-antitrypsin deficiency	2022-07-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 247 of the SERPINA1 protein (p.Arg247Cys). This variant is present in population databases (rs28929470, gnomAD 0.4%). This missense change has been observed in individual(s) with chronic obstructive pulmonary disease (COPD) and slight decreased A1AT protein levels and alpha 1-antitrypsine (A1AT) deficiency (PMID: 2035534, 22078084). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as allele F or p.Arg223Cys. ClinVar contains an entry for this variant (Variation ID: 17961). 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. Experimental studies have shown that this missense change affects SERPINA1 function (PMID: 8912354). 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000727618	SCV005046904	pathogenic	not provided	2022-10-05	criteria provided, single submitter	clinical testing
OMIM	RCV000019561	SCV000039858	other	PI F	2016-07-15	no assertion criteria provided	literature only
CSER _CC_NCGL, University of Washington	RCV000148879	SCV000190623	uncertain significance	Alpha-1-antitrypsin deficiency	2014-06-01	no assertion criteria provided	research
GeneReviews	RCV000148879	SCV000256628	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	RCV000148879	SCV000608326	likely pathogenic	Alpha-1-antitrypsin deficiency	2014-12-08	no assertion criteria provided	clinical testing	Mildly reduced alpha-1-antitrypsin activity. In practice appears to be associated with mild deficiency. Literature opinion divided. Protein levels may be normal but has a decreased ability to inhibit neutrophil elastase & is frequently seen in patients with respiratory symptoms.
PreventionGenetics, part of Exact Sciences	RCV004724750	SCV005337700	uncertain significance	SERPINA1-related disorder	2024-09-09	no assertion criteria provided	clinical testing	The SERPINA1 c.739C>T variant is predicted to result in the amino acid substitution p.Arg247Cys. This variant has been reported in the literature, but its pathogenicity was not fully understood (Supplementary Table 1 at Amendola et al. 2015. PubMed ID: 25637381; Table S5 at Maxwell et al. 2016. PubMed ID: 27153395). This variant is also known as the F allele or p.Arg223Cys, and is reported to have decreased binding affinity and inhibitory capacity against elastase resulting in lung but not liver disease (Giacopuzzi et al. 2018. PubMed ID: 29882371). This variant is reported in 0.42% of alleles in individuals of European (Non-Finnish) descent), including one homozygous observation. In summary, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.