rs61761869

Variant names:

• chr14-94378529-G-A
• rs61761869
• NM_000295.5:c.1177C>T

Your query was ambiguous. Multiple possible variants found:

• chr14-94378529-G-A
• chr14-94378529-G-C
• chr14-94378529-G-T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM5 PP3_Strong PP5_Very_Strong

The NM_000295.5(SERPINA1):​c.1177C>T​(p.Pro393Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000357 in 1,614,126 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P393T) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00036 (0 hom.)
• Consequence: SERPINA1 NM_000295.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14 U:1
• Conservation: PhyloP100: 8.72
• Publications: 32 publications found

Genes affected

SERPINA1 (HGNC:8941): (serpin family A member 1) The protein encoded by this gene is a serine protease inhibitor belonging to the serpin superfamily whose targets include elastase, plasmin, thrombin, trypsin, chymotrypsin, and plasminogen activator. This protein is produced in the liver, the bone marrow, by lymphocytic and monocytic cells in lymphoid tissue, and by the Paneth cells of the gut. Defects in this gene are associated with chronic obstructive pulmonary disease, emphysema, and chronic liver disease. Several transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Aug 2020]

SERPINA1 Gene-Disease associations (from GenCC):

• alpha 1-antitrypsin deficiency

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
• hemorrhagic disease due to alpha-1-antitrypsin Pittsburgh mutation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• cystic fibrosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-94378529-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 219360.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.951
• PP5: Variant 14-94378529-G-A is Pathogenic according to our data. Variant chr14-94378529-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 289135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000295.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINA1	NM_000295.5	MANE Select	c.1177C>T	p.Pro393Ser	missense	Exon 5 of 5	NP_000286.3
	SERPINA1	NM_001002235.3		c.1177C>T	p.Pro393Ser	missense	Exon 5 of 5	NP_001002235.1
	SERPINA1	NM_001002236.3		c.1177C>T	p.Pro393Ser	missense	Exon 7 of 7	NP_001002236.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINA1	ENST00000393087.9	TSL:1 MANE Select	c.1177C>T	p.Pro393Ser	missense	Exon 5 of 5	ENSP00000376802.4
	SERPINA1	ENST00000355814.8	TSL:1	c.1177C>T	p.Pro393Ser	missense	Exon 5 of 5	ENSP00000348068.4
	SERPINA1	ENST00000393088.8	TSL:1	c.1177C>T	p.Pro393Ser	missense	Exon 7 of 7	ENSP00000376803.4

Frequencies

GnomAD3 genomes AF: 0.000316 AC: 48 AN: 152126 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000290 AC: 73 AN: 251474 AF XY: 0.000353

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000536

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000362 AC: 529 AN: 1461880 Hom.: 0 Cov.: 33 AF XY: 0.000385 AC XY: 280 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000179 AC: 8 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5768

European-Non Finnish (NFE) AF: 0.000433 AC: 481 AN: 1111998

Other (OTH) AF: 0.000447 AC: 27 AN: 60396

GnomAD4 genome AF: 0.000315 AC: 48 AN: 152246 Hom.: 0 Cov.: 33 AF XY: 0.000376 AC XY: 28 AN XY: 74428

African (AFR) AF: 0.0000963 AC: 4 AN: 41542

American (AMR) AF: 0.000196 AC: 3 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000588 AC: 40 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000550 Hom.: 1

Bravo AF: 0.000317

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000272 AC: 33

EpiCase AF: 0.00109

EpiControl AF: 0.000830

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alpha-1-antitrypsin deficiency Pathogenic:9 Uncertain:1

Mar 29, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 14, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 30, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is present in gnomAD <0.01 for a recessive condition (v2) (81 heterozygotes, 0 homozygotes); This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is also known as p.(Pro369Leu) in an alternative nomenclature or as the MWurzburg allele. It has previously been reported in at least 8 alpha-1-1-antitrypsin deficiency patients and is often referred to as a severe deficient allele (ClinVar; PMIDs: 27296815; 18024524; 18515255; 11474657; 19437508; 10878477); This variant has moderate functional evidence supporting abnormal protein function. In vitro and in vivo functional studies have demonstrated that this variant results in intracellular transportation and secretion defects (PMID: 10234508; 22723858); Another missense variants comparable to the one identified in this case have limited previous evidence for pathogenicity. The p.(Pro393Leu) (alternatively known as P369L or MHeerlen) has previously been reported in at least 5 patients and has been suggested to result in extremely low AAT level and no liver disease (ClinVar; PMID: 26321041; 2784123; 27296815; 10234508). In addition, p.(Pro393His) has previously been reported in an adult female patient (compound heterozygote with the 'S' allele) suspected of having AATD however AAT serum level was normal (PMID: 31307431) and p.(Pro393Thr) was previously reported as pathogenic and as a variant of uncertain significance once each in ClinVar; Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. Additional information: Variant is predicted to result in a missense amino acid change from proline to serine; This variant is heterozygous; This gene is associated with autosomal recessive disease; Multiple alternative amino acid changes at the same position has been observed in gnomAD (v2) with p.(Pro393Leu) having the highest allele count (14 heterozygotes, 0 homozygotes); Variant is located in the annotated reactive centre loop (RCL) within the Serpin domain (NCBI conserved domains; Pfam); Loss of function is a known mechanism of disease in this gene and is associated with alpha 1-antitrypsin deficiency (MONDO:0013282), SERPINA1-related; Heterozygous variant detected in trans with a second PATHOGENIC heterozygous variant (NM_000295.5(SERPINA1):c.1158dup; p.(Glu387Argfs*14)) in a recessive disease; This variant has been shown to be maternally inherited (by trio analysis).

Dec 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 393 of the SERPINA1 protein (p.Pro393Ser). This variant is present in population databases (rs61761869, gnomAD 0.05%). This missense change has been observed in individuals with alpha-1-antitrypsin deficiency (AATD) (PMID: 18024524, 27296815). ClinVar contains an entry for this variant (Variation ID: 289135). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt SERPINA1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects SERPINA1 function (PMID: 10234508, 27296815). 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: 2784123, 10234508, 27296815). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 23, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SERPINA1 c.1177C>T (p.Pro393Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 251474 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in SERPINA1 causing Alpha-1-Antitrypsin Deficiency (0.00029 vs 0.005), allowing no conclusion about variant significance. c.1177C>T has been reported in the literature in individuals affected with Alpha-1-Antitrypsin Deficiency (e.g. Jardi_2000, Print_2008, Silva_2016, Scioscia_2024). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in a complete intracellular transport block in cell cultures in vitro (Poller_1999). The following publications have been ascertained in the context of this evaluation (PMID: 18024524, 27296815, 10878477, 10234508, 38876920). ClinVar contains an entry for this variant (Variation ID: 289135). Based on the evidence outlined above, the variant was classified as pathogenic.

Aug 17, 2018

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Aug 04, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

May 13, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Oct 01, 2021

Myriad Genetics, Inc.

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

NM_000295.4(SERPINA1):c.1177C>T(P393S) is a missense variant classified as a variant of uncertain significance in the context of alpha-1 antitrypsin deficiency. P393S has been observed in cases with relevant disease (PMID: 19437508, 18515255, 10878477, 10234508, 27296815, 21474916, 19654085). Functional assessments of this variant are available in the literature (PMID: 22723858, 10234508). P393S has been observed in population frequency databases (gnomAD: NFE 0.05%). In summary, there is insufficient evidence to classify NM_000295.4(SERPINA1):c.1177C>T(P393S) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.

not provided Pathogenic:4

May 09, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as P369S or Mwurzburg allele using alternate nomenclature; This variant is associated with the following publications: (PMID: 31980526, 10234508, 27296815, 11474657, 31447099, 34426522, 34308104, 31661293, 21228398, 29882371, 38791420, 37688579, 22723858)

Aug 09, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 13, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PP4, PM2_moderate, PM5, PS3

May 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SERPINA1: PM3:Strong, PM1, PM2, PM5, PP4:Moderate, PS3:Supporting

SERPINA1-related disorder Pathogenic:1

Mar 08, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SERPINA1 c.1177C>T variant is predicted to result in the amino acid substitution p.Pro393Ser. This variant has been reported to be pathogenic for autosomal recessive alpha1-antitrypsin deficiency (Giacopuzzi et al. 2018. PubMed ID: 29882371; Ortega et al. 2019. PubMed ID: 31661293). It is known as the M (Würzburg) allele in the literature. This variant is reported in 0.053% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Taken together, this variant is reported as pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.54
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.050	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		8.7
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-7.3	D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.033	D
Polyphen		1.0	D
Vest4		0.83
MVP		1.0
MPC		0.31
ClinPred		0.96	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.63
gMVP		0.77
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs61761869; hg19: chr14-94844866;