NM_000295.5(SERPINA1):c.1178C>G (p.Pro393Arg) AND Alpha-1-antitrypsin deficiency

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Oct 3, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001377892.9

Allele description [Variation Report for NM_000295.5(SERPINA1):c.1178C>G (p.Pro393Arg)]

NM_000295.5(SERPINA1):c.1178C>G (p.Pro393Arg)

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.1178C>G (p.Pro393Arg)

HGVS:

NC_000014.9:g.94378528G>C
NG_008290.1:g.17165C>G
NM_000295.5:c.1178C>GMANE SELECT
NM_001002235.3:c.1178C>G
NM_001002236.3:c.1178C>G
NM_001127700.2:c.1178C>G
NM_001127701.2:c.1178C>G
NM_001127702.2:c.1178C>G
NM_001127703.2:c.1178C>G
NM_001127704.2:c.1178C>G
NM_001127705.2:c.1178C>G
NM_001127706.2:c.1178C>G
NM_001127707.2:c.1178C>G
NP_000286.3:p.Pro393Arg
NP_001002235.1:p.Pro393Arg
NP_001002236.1:p.Pro393Arg
NP_001121172.1:p.Pro393Arg
NP_001121173.1:p.Pro393Arg
NP_001121174.1:p.Pro393Arg
NP_001121175.1:p.Pro393Arg
NP_001121176.1:p.Pro393Arg
NP_001121177.1:p.Pro393Arg
NP_001121178.1:p.Pro393Arg
NP_001121179.1:p.Pro393Arg
LRG_575t1:c.1178C>G
LRG_575:g.17165C>G
LRG_575p1:p.Pro393Arg
NC_000014.8:g.94844865G>C

Protein change:

P393R

Links:

dbSNP: rs199422209

NCBI 1000 Genomes Browser:

rs199422209

Molecular consequence:

NM_000295.5:c.1178C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001002235.3:c.1178C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001002236.3:c.1178C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001127700.2:c.1178C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001127701.2:c.1178C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001127702.2:c.1178C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001127703.2:c.1178C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001127704.2:c.1178C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001127705.2:c.1178C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001127706.2:c.1178C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001127707.2:c.1178C>G - missense variant - [Sequence Ontology: SO:0001583]

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001575341	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Oct 3, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 10234508, 18024524, 27296815, 28492532
SCV002556655	Genetics and Molecular Pathology, SA Pathology See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 5, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 10234508, 18024524, 27296815, 25741868
SCV004848684	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 30, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001575341

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Oct 3, 2022)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV002556655

Genetics and Molecular Pathology, SA Pathology

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Apr 5, 2022)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV004848684

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jun 30, 2022)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical 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

Molecular characterisation of the defective alpha 1-antitrypsin alleles PI Mwurzburg (Pro369Ser), Mheerlen (Pro369Leu), and Q0lisbon (Thr68Ile).

Poller W, Merklein F, Schneider-Rasp S, Haack A, Fechner H, Wang H, Anagnostopoulos I, Weidinger S.

Eur J Hum Genet. 1999 Apr;7(3):321-31.

PubMed [citation]

PMID:: 10234508

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001575341.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Pro393 amino acid residue in SERPINA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10234508, 18024524, 27296815). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 1066793). This variant has not been reported in the literature in individuals affected with SERPINA1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 393 of the SERPINA1 protein (p.Pro393Arg).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genetics and Molecular Pathology, SA Pathology, SCV002556655.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

The SERPINA1 c.1178C>G variant is classified as LIKELY PATHOGENIC (PS4, PM5, PP3) The SERPINA1 c.1178C>G variant is a single nucleotide change in exon 5/5 of the SERPINA1 gene, which is predicted to change the amino acid proline at position 393 in the protein to arginine. The variant has been reported in a patient with Alpha-1-antitrypsin deficiency (PS4) and similar missense variants affecting the same residue have also been reported as pathogenic (PMID:27296815, 18024524, 10234508, 27296815), suggesting that this residue is clinically significant (PM5). Computational predictions support a deleterious effect on the gene or gene product (PP3). The variant has been reported in dbSNP (rs199422209) and has been reported as likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 1066793). It has not been reported in HGMD.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004848684.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

The p.Pro393Arg variant in SERPINA1 has not been reported in individuals with SERPINA1-related phenotypes including alpha-1 antitrypsin deficiency and was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Two additional variants involving this codon (p.Pro393Leu, p.Pro393Ser) have been identified in individuals with SERPINA1-related phenotypes, suggesting that this codon is intolerant to variation. In summary, although additional studies are required to fully establish its clinical significance, the p.Pro393Arg variant likely pathogenic for autosomal recessive alpha-1 antitrypsin deficiency. ACMG/AMP Criteria applied: PM5_S, PP3, PM2_P.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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