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NM_000295.5(SERPINA1):c.899T>G (p.Leu300Arg) AND Alpha-1-antitrypsin deficiency

Germline classification:
Likely benign (2 submissions)
Last evaluated:
Jan 21, 2024
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV001083682.10

Allele description [Variation Report for NM_000295.5(SERPINA1):c.899T>G (p.Leu300Arg)]

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

Gene:
SERPINA1:serpin family A member 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
14q32.13
Genomic location:
Preferred name:
NM_000295.5(SERPINA1):c.899T>G (p.Leu300Arg)
HGVS:
  • NC_000014.9:g.94380889A>C
  • NG_008290.1:g.14804T>G
  • NM_000295.5:c.899T>GMANE SELECT
  • NM_001002235.3:c.899T>G
  • NM_001002236.3:c.899T>G
  • NM_001127700.2:c.899T>G
  • NM_001127701.2:c.899T>G
  • NM_001127702.2:c.899T>G
  • NM_001127703.2:c.899T>G
  • NM_001127704.2:c.899T>G
  • NM_001127705.2:c.899T>G
  • NM_001127706.2:c.899T>G
  • NM_001127707.2:c.899T>G
  • NP_000286.3:p.Leu300Arg
  • NP_001002235.1:p.Leu300Arg
  • NP_001002236.1:p.Leu300Arg
  • NP_001121172.1:p.Leu300Arg
  • NP_001121173.1:p.Leu300Arg
  • NP_001121174.1:p.Leu300Arg
  • NP_001121175.1:p.Leu300Arg
  • NP_001121176.1:p.Leu300Arg
  • NP_001121177.1:p.Leu300Arg
  • NP_001121178.1:p.Leu300Arg
  • NP_001121179.1:p.Leu300Arg
  • LRG_575t1:c.899T>G
  • LRG_575:g.14804T>G
  • LRG_575p1:p.Leu300Arg
  • NC_000014.8:g.94847226A>C
  • NM_000295.4:c.899T>G
Protein change:
L300R
Links:
dbSNP: rs550592374
NCBI 1000 Genomes Browser:
rs550592374
Molecular consequence:
  • NM_000295.5:c.899T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001002235.3:c.899T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001002236.3:c.899T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001127700.2:c.899T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001127701.2:c.899T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001127702.2:c.899T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001127703.2:c.899T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001127704.2:c.899T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001127705.2:c.899T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001127706.2:c.899T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001127707.2:c.899T>G - missense variant - [Sequence Ontology: SO:0001583]
Functional consequence:
variation affecting protein structure [Variation Ontology: 0060]
Observations:
1

Condition(s)

Name:
Alpha-1-antitrypsin deficiency (A1ATD)
Synonyms:
AAT deficiency; A1AT deficiency; Alpha1-Antitrypsin Deficiency
Identifiers:
MONDO: MONDO:0013282; MedGen: C0221757; Orphanet: 60; OMIM: 613490

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001005039Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Likely benign
(Jan 21, 2024) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002568442Instituto Universitario de Enfermedades Tropicales y Salud Pública de Canarias, University of La Laguna
no assertion criteria provided
Pathogenic
(Aug 30, 2022) 		inheritedclinical testing

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
Chineseinheritedyes1not providednot providednot providednot providedclinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001005039.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Instituto Universitario de Enfermedades Tropicales y Salud Pública de Canarias, University of La Laguna, SCV002568442.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1Chinese1not providednot providedclinical testingnot provided

Description

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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1inheritedyesnot providednot providednot provided1not providednot providednot provided

Last Updated: Sep 29, 2024