ClinVar Miner

Submissions for variant NM_001127701.1(SERPINA1):c.839A>T (p.Asp280Val) (rs121912714)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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
Invitae RCV000148876 SCV000948693 pathogenic Alpha-1-antitrypsin deficiency 2020-10-23 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with valine at codon 280 of the SERPINA1 protein (p.Asp280Val). The aspartic acid residue is weakly conserved and there is a large physicochemical difference between aspartic acid and valine. This variant is present in population databases (rs121912714, ExAC 0.07%). This variant, also referred to as PI*Lowell allele, PI*Duarte allele, or PI*Null Cardiff allele, has been observed to segregate with alpha-1 antitrypsin deficiency (AATD) in families (PMID: 2240842, 2831367), and has been observed in individuals affected with AATD (PMID: 8364590, 27296815, 26321041, 17906067, 15744045, 2787118). This variant is also known as p.Asp256Val in the literature. ClinVar contains an entry for this variant (Variation ID: 17975). Experimental studies have shown that this missense change disrupts protein folding and reduces secretion of alpha-1 antitrypsin due to intracellular degradation (PMID: 2240842, 14767073,15949707). For these reasons, this variant has been classified as Pathogenic.
Mendelics RCV000148876 SCV001139504 uncertain significance Alpha-1-antitrypsin deficiency 2019-05-28 criteria provided, single submitter clinical testing
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.

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