Submissions for variant NM_001127701.1(SERPINA1):c.839A>T (p.Asp280Val)

gnomAD frequency: 0.00033  dbSNP: rs121912714

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000398063	SCV000342428	other	not provided	2016-06-22	criteria provided, single submitter	clinical testing
Counsyl	RCV000148876	SCV000485285	likely pathogenic	Alpha-1-antitrypsin deficiency	2016-03-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000148876	SCV000948693	pathogenic	Alpha-1-antitrypsin deficiency	2025-01-14	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 280 of the SERPINA1 protein (p.Asp280Val). This variant is present in population databases (rs121912714, gnomAD 0.3%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with alpha-1 antitrypsin deficiency (AATD) (PMID: 2240842, 2787118, 2831367, 8364590, 15744045, 17906067, 26321041, 27296815). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Asp256Val, PI*Lowell allele, PI*Duarte allele, or PI*Null Cardiff allele. ClinVar contains an entry for this variant (Variation ID: 17975). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SERPINA1 protein function. Experimental studies have shown that this missense change affects SERPINA1 function (PMID: 2240842, 14767073, 15949707). For these reasons, this variant has been classified as Pathogenic.
Mendelics	RCV000148876	SCV001139504	pathogenic	Alpha-1-antitrypsin deficiency	2022-08-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000398063	SCV001875198	pathogenic	not provided	2023-11-28	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect due to impaired secretion of mutant protein (PMID: 15949707, 2240842); 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: 14767073, 31661293, 2787118, 21474916, 8364590, 1504305, 25637381, 2606478, 2696185, 15744045, 2831367, 2240842, 17906067, 26321041, 29882371, 27296815, 26987331, 27264265, 31447099, 31980526, 34426522, 31589614, 34308104, 34828384, 15949707, 27535533)
Revvity Omics, Revvity	RCV000148876	SCV002020068	pathogenic	Alpha-1-antitrypsin deficiency	2020-02-07	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000148876	SCV004203112	pathogenic	Alpha-1-antitrypsin deficiency	2024-03-30	criteria provided, single submitter	clinical testing
Institute of Immunology and Genetics Kaiserslautern	RCV000148876	SCV004803202	pathogenic	Alpha-1-antitrypsin deficiency	2024-03-12	criteria provided, single submitter	clinical testing	ACMG Criteria: PS3, PS4_M, PM3, PP3, PP5; Individual was compound heterozygous for SERPINA1 variants c.839A>T and c.1096G>A
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000148876	SCV005381643	pathogenic	Alpha-1-antitrypsin deficiency	2024-08-01	criteria provided, single submitter	clinical testing	Variant summary: SERPINA1 c.839A>T (p.Asp280Val) results in a non-conservative amino acid change located in the Serpin domain (IPR023796) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00047 in 251490 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SERPINA1 causing Alpha-1-Antitrypsin Deficiency (0.00047 vs 0.005), allowing no conclusion about variant significance. c.839A>T has been reported in the literature in multiple individuals affected with Alpha-1-Antitrypsin Deficiency (examples: Faber_1989, Holmes_1990,Grahm_2015, Silva_2016,Ortega_2020). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence that this variant causes a protein folding defect (Jung_2004). The following publications have been ascertained in the context of this evaluation (PMID: 14767073, 2240842, 2787118, 27296815, 31661293, 26321041). ClinVar contains an entry for this variant (Variation ID: 17975). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000019576	SCV000039873	other	PI P(LOWELL)	2016-07-15	no assertion criteria provided	literature only
OMIM	RCV000019577	SCV000039874	other	PI NULL(CARDIFF)	2016-07-15	no assertion criteria provided	literature only
OMIM	RCV000019578	SCV000039875	other	PI Q0(CARDIFF)	2016-07-15	no assertion criteria provided	literature only
OMIM	RCV000019605	SCV000039903	other	PI P(DUARTE)	2016-07-15	no assertion criteria provided	literature only
CSER _CC_NCGL, University of Washington	RCV000148876	SCV000190620	likely pathogenic	Alpha-1-antitrypsin deficiency	2014-06-01	no assertion criteria provided	research
Department of Laboratory Medicine and Genetics, Trillium Health Partners Credit Valley Hospital	RCV000148876	SCV000608329	pathogenic	Alpha-1-antitrypsin deficiency	2014-12-08	no assertion criteria provided	curation
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000398063	SCV001552512	likely pathogenic	not provided		no assertion criteria provided	clinical testing	The SERPINA1 p.Asp280Val variant, often referred to as the Plowell protein variant, was identified in 12 of 248 proband chromosomes (2 homozygotes, frequency: 0.048) from individuals or families with alpha1-antitrypsin deficiency (AATD) and was not identified in 1500 control chromosomes from individuals with normal AAT serum levels (Graham_2015_PMID:26321041; Corda_2011_PMID:21474916; Bornhorst_2007_PMID:17906067). The variant was also identified in dbSNP (ID: rs121912714), LOVD 3.0 and in ClinVar (classified as pathogenic by Trillium Health Partners Credit Valley Hospital, likely pathogenic by Counsyl and CSER_CC_NCGL, University of Washington Medical Center, and 'other' by EGL Genetic Diagnostics). The variant was not identified in Cosmic. The variant was identified in control databases in 129 of 282876 chromosomes at a frequency of 0.000456 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 35 of 10370 chromosomes (freq: 0.003375), Latino in 20 of 35438 chromosomes (freq: 0.000564), Other in 4 of 7226 chromosomes (freq: 0.000554), European (non-Finnish) in 68 of 129190 chromosomes (freq: 0.000526) and South Asian in 2 of 30616 chromosomes (freq: 0.000065); it was not observed in the African, East Asian and European (Finnish) populations. Functional studies of the D280V variant have suggested increased intracellular protein degradation and have demonstrated delayed secretion of the AAT protein, with only the secreted form producing a stable SDS-complex with elastase while the intracellular form demonstrated reduced ability to form a stable complex. However little differences in stability to urea denaturation were observed compared to the wildtype (Ray_2006_PMID: 15949707; Holmes_1990_PMID:2240842). Another functional study found that the D280V variant caused delayed protein folding, however the stability and inhibitory activity of the protein was similar to wildtype once protein folding did occur (Jung_2004_PMID: 14767073). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Asp280 residue is not highly conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003415723	SCV004116044	pathogenic	SERPINA1-related disorder	2024-02-20	no assertion criteria provided	clinical testing	The SERPINA1 c.839A>T variant is predicted to result in the amino acid substitution p.Asp280Val. This variant has been reported to be causative for autosomal recessive alpha-1-antitrypsin deficiency (Silva et al 2016. PubMed ID: 27296815, reported as p.Asp256Val; Graham et al 2015. PubMed ID: 26321041). This variant is reported in 0.34% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as pathogenic.