Submissions for variant NM_001127701.1(SERPINA1):c.194T>C (p.Leu65Pro)

gnomAD frequency: 0.00004  dbSNP: rs28931569

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000201848	SCV000788706	likely pathogenic	Alpha-1-antitrypsin deficiency	2016-12-28	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000729804	SCV000857495	pathogenic	not provided	2017-10-17	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000201848	SCV000893355	likely pathogenic	Alpha-1-antitrypsin deficiency	2022-01-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000201848	SCV000961591	pathogenic	Alpha-1-antitrypsin deficiency	2024-10-14	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 65 of the SERPINA1 protein (p.Leu65Pro). This variant is present in population databases (rs28931569, gnomAD 0.009%). This missense change has been observed in individual(s) with alpha 1-antitrypsin deficiency (PMID: 3262617, 9635295). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as M procida and p.Leu41Pro. ClinVar contains an entry for this variant (Variation ID: 17971). 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: 14767073). For these reasons, this variant has been classified as Pathogenic.
Mendelics	RCV000201848	SCV001139507	likely pathogenic	Alpha-1-antitrypsin deficiency	2019-05-28	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000201848	SCV002019173	likely pathogenic	Alpha-1-antitrypsin deficiency	2020-04-05	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University Hospital Muenster	RCV004584332	SCV002054118	likely pathogenic	See cases	2021-12-05	criteria provided, single submitter	clinical testing	ACMG categories: PM1,PM2,PP3,PP5
Baylor Genetics	RCV000201848	SCV004203115	likely pathogenic	Alpha-1-antitrypsin deficiency	2024-03-22	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000201848	SCV005086285	likely pathogenic	Alpha-1-antitrypsin deficiency	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with alpha-1-antitrypsin deficiency (MIM#613490). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from leucine to proline. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 14 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated Serpin domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. Also known as MPorcida allele or Leu41Pro in the literature, it has been reported in alpha-1-antitrypsin deficient patients, including those who were compound heterozygotes with null alleles (PMID: 1975477, 9635295; ClinVar). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Mutant protein has been showed to have retarded protein folding and were unable to form inhibitory complexes with target protease (PMID: 14767073). (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_000295.4:c.559A>T; p.(Lys187*)) in a recessive disease. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000019571	SCV000039868	other	PI M(PROCIDA)	2016-07-15	no assertion criteria provided	literature only
GeneReviews	RCV000201848	SCV000256622	pathogenic	Alpha-1-antitrypsin deficiency	2014-05-01	no assertion criteria provided	literature only
Department of Laboratory Medicine and Genetics, Trillium Health Partners Credit Valley Hospital	RCV000201848	SCV000608305	pathogenic	Alpha-1-antitrypsin deficiency	2014-12-08	no assertion criteria provided	curation	Reduced enzyme activity