NM_000295.5(SERPINA1):c.1177C>T (p.Pro393Ser) AND Alpha-1-antitrypsin deficiency

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(2);Pathogenic(1);Uncertain significance(1) (Last evaluated: Oct 7, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
4 submissions [Details]
Record status:
current
Accession:
RCV000336993.11

Allele description [Variation Report for NM_000295.5(SERPINA1):c.1177C>T (p.Pro393Ser)]

NM_000295.5(SERPINA1):c.1177C>T (p.Pro393Ser)

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.1177C>T (p.Pro393Ser)
HGVS:
  • NC_000014.9:g.94378529G>A
  • NG_008290.1:g.17164C>T
  • NM_000295.5:c.1177C>TMANE SELECT
  • NM_001002235.3:c.1177C>T
  • NM_001002236.3:c.1177C>T
  • NM_001127700.2:c.1177C>T
  • NM_001127701.2:c.1177C>T
  • NM_001127702.2:c.1177C>T
  • NM_001127703.2:c.1177C>T
  • NM_001127704.2:c.1177C>T
  • NM_001127705.2:c.1177C>T
  • NM_001127706.2:c.1177C>T
  • NM_001127707.2:c.1177C>T
  • NP_000286.3:p.Pro393Ser
  • NP_001002235.1:p.Pro393Ser
  • NP_001002236.1:p.Pro393Ser
  • NP_001121172.1:p.Pro393Ser
  • NP_001121173.1:p.Pro393Ser
  • NP_001121173.1:p.Pro393Ser
  • NP_001121174.1:p.Pro393Ser
  • NP_001121175.1:p.Pro393Ser
  • NP_001121176.1:p.Pro393Ser
  • NP_001121177.1:p.Pro393Ser
  • NP_001121178.1:p.Pro393Ser
  • NP_001121179.1:p.Pro393Ser
  • LRG_575t1:c.1177C>T
  • LRG_575:g.17164C>T
  • LRG_575p1:p.Pro393Ser
  • NC_000014.8:g.94844866G>A
  • NM_000295.4:c.1177C>T
  • NM_001127701.1:c.1177C>T
Protein change:
P393S
Links:
dbSNP: rs61761869
NCBI 1000 Genomes Browser:
rs61761869
Molecular consequence:
  • NM_000295.5:c.1177C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001002235.3:c.1177C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001002236.3:c.1177C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001127700.2:c.1177C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001127701.2:c.1177C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001127702.2:c.1177C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001127703.2:c.1177C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001127704.2:c.1177C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001127705.2:c.1177C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001127706.2:c.1177C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001127707.2:c.1177C>T - missense variant - [Sequence Ontology: SO:0001583]
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

Recent activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000630387Invitaecriteria provided, single submitter
Pathogenic
(Oct 7, 2020)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV000711354Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicinecriteria provided, single submitter
Likely pathogenic
(May 13, 2017)
germlineclinical testing

PubMed (9)
[See all records that cite these PMIDs]

SCV000800690Counsylcriteria provided, single submitter
Uncertain significance
(Apr 3, 2018)
unknownclinical testing

PubMed (7)
[See all records that cite these PMIDs]

Citation Link,

SCV000915659Illumina Clinical Services Laboratory,Illuminacriteria provided, single submitter
Likely pathogenic
(Aug 17, 2018)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot provided11not providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Inherited chronic obstructive pulmonary disease: new selective-sequencing workup for alpha1-antitrypsin deficiency identifies 2 previously unidentified null alleles.

Prins J, van der Meijden BB, Kraaijenhagen RJ, Wielders JP.

Clin Chem. 2008 Jan;54(1):101-7. Epub 2007 Nov 16.

PubMed [citation]
PMID:
18024524

A Pro----Leu substitution in codon 369 of the alpha-1-antitrypsin deficiency variant PI MHeerlen.

Hofker MH, Nukiwa T, van Paassen HM, Nelen M, Kramps JA, Klasen EC, Frants RR, Crystal RG.

Hum Genet. 1989 Feb;81(3):264-8.

PubMed [citation]
PMID:
2784123
See all PubMed Citations (15)

Details of each submission

From Invitae, SCV000630387.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This sequence change replaces proline with serine at codon 393 of the SERPINA1 protein (p.Pro393Ser). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs61761869, ExAC 0.04%). This variant has been reported in the literature as a compound heterozygous in individuals affected with alpha-1-antitrypsin deficiency (AATD) (PMID: 27296815, 18024524). This variant is also known in the literature as MWurzburg and as Pro369Ser. ClinVar contains an entry for this variant (Variation ID: 289135). Experimental studies have shown that this missense change causes a dramatic reduction of the levels of SERPINA1 enzyme levels in vitro (PMID: 10234508, 27296815) and in vivo (PMID: 10234508). A different missense substitution at this codon (p.Pro393Leu) has been determined to be pathogenic (PMID: 2784123, 10234508, 27296815). This suggests that the proline residue is critical for SERPINA1 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, SCV000711354.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (9)

Description

The p.Pro393Ser variant in SERPINA1 (MWurzburg allele) has been reported in at l east 5 individuals with SERPINA1-related phenotypes, including alpha-1-antitryps in deficiency (AATD), asthma, elevated transaminases, and intrahepatic inclusion s (Poller 1999, Sexias 2001, Medicina 2009, Silva 2016, and Denden 2009). Three of these individuals were heterozygous, while 2 individuals with liver phenotype s were compound heterozygous. The variant segregated in at least 1 family member with low levels of alpha-1-antritrypsin and 2 members of 1 family with asthma ( Poller 1999, Denden 2009). In vitro and in vivo functional studies provide some evidence that the p.Pro393Ser variant may impact protein function; however, thes e types of assays may not accurately represent biological function (Poller 1999, Fra 2012). This variant has also been identified in 29/66728 European chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs61761869); however, this frequency is low enough to be consistent with a r ecessive carrier frequency. Furthermore, a different variant at the same positio n (p.Pro393Leu) has been classified as pathogenic by our laboratory, supporting that a change at this position may not be tolerated. In summary, although additi onal studies are required to fully establish its clinical significance, the p.Pr o393Ser variant is likely pathogenic.

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

From Counsyl, SCV000800690.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Illumina Clinical Services Laboratory,Illumina, SCV000915659.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

The SERPINA1 c.1177C>T (p.Pro393Ser) variant, also referred to as Pi-M(Wurzburg), has been identified in a compound heterozygous state in three patients with alpha-1 antitrypsin deficiency (AATD) (Seixas et al. 2001; Medicina et al. 2009; Zorzetto et al. 2008). Control data are unavailable for this variant, which is reported at a frequency of 0.000513 in the European (non-Finnish) population of the Genome Aggregation Database. Poller et al. (1999) performed in vitro and in vivo functional studies and demonstrated that the p.Pro393Ser variant had defective intracellular transport and secretion into the bloodstream compared to the wild type AAT protein. The Pro393 residue is predicted to form part of a critical domain of the AAT protein. Based on the evidence, the p.Pro393Ser variant is classified as likely pathogenic for alpha-1 antitrypsin deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jul 7, 2021

Support Center