ClinVar Miner

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

gnomAD frequency: 0.00211  dbSNP: rs28929470
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Total submissions: 12
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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 ( 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 2023-05-08 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 (Okayama et al., 1991; Ringenbach et al., 2011; Sinden et al., 2014); 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) (Sinden et al., 2014); 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, 25098359, 2035534, 9041988, 15115878, 29882371, 26310624, 23632999, 6306478, Wang2022[Functional Study], 20301692, 31819391, 32181528, 31450843, 26647313, 31661293, 35477570)
MGZ Medical Genetics Center RCV000148879 SCV002579104 likely pathogenic Alpha-1-antitrypsin deficiency 2022-04-11 criteria provided, single submitter clinical testing
Invitae 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.
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.

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