ClinVar Miner

Submissions for variant NM_000295.5(SERPINA1):c.899T>G (p.Leu300Arg)

gnomAD frequency: 0.00009  dbSNP: rs550592374
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000729755 SCV000857442 uncertain significance not provided 2017-10-10 criteria provided, single submitter clinical testing
Invitae RCV001083682 SCV001005039 likely benign Alpha-1-antitrypsin deficiency 2024-01-21 criteria provided, single submitter clinical testing
Ambry Genetics RCV002369991 SCV002683738 uncertain significance Inborn genetic diseases 2015-06-22 criteria provided, single submitter clinical testing The p.L300R variant (also known as c.899T>G), located in coding exon 2 of the SERPINA1 gene, results from a T to G substitution at nucleotide position 899. The leucine at codon 300 is replaced by arginine, an amino acid with dissimilar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species on limited alignment. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Instituto Universitario de Enfermedades Tropicales y Salud Pública de Canarias, University of La Laguna RCV001083682 SCV002568442 pathogenic Alpha-1-antitrypsin deficiency 2022-08-30 no assertion criteria provided clinical testing Serum alpha-1-antitrypsin (AAT) levels, AAT phenotypes, and sequences of SERPINA1 gene were examined in a Chinese child with a moderate deficit of serum AAT, who had suffered several episodes of liver disease, as well as in his first-order relatives. Results allowed the identification of PI*S-hangzhou, a novel SERPINA1 defective allele, which has been characterized by a L276R substitution (in mature AAT) , found in a SERPINA1-M3 genetic background. The index case was admitted to the hospital due to severe jaundice, with elevated plasma levels of total bilirubin (20.4 mg/dl) and gamma-glutamyl transpeptidase (139 U/l). IEF analysis of AAT pointed out a PiMS phenotype, with AAT concentration (81.3 mg/dl) below the reference ranges described for PiMS phenotype. Potential effects of PI*Shangzhou mutation over the AAT structure were studied by 3D homology modelling. The presence of an arginine residue at position 276 could destabilize the tertiary structure of AAT, since it occurs at a highly conserved hydrophobic cavity in the protein surface, and very close to two positively-charged amino acids: K243 and K380. Therefore, the electrostatic repulsion between R276 and K243/K380 residues could destabilize the tertiary structure of mutant AAT. Attending to the frequency of R276 variant reported in databases for individuals of East Asian ancestry, the PI*Shangzhou allele may explain the global prevalence of the PiS phenotype observed in China.

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