Submissions for variant NM_000295.5(SERPINA1):c.221TCT[2] (p.Phe76del)

dbSNP: rs775982338

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000262058	SCV000389657	pathogenic	Alpha-1-antitrypsin deficiency	2017-04-27	criteria provided, single submitter	clinical testing	The SERPINA1 c.227_229delTCT (p.Phe76del) variant is an inframe deletion variant which is often described in the literature as p.Phe51del, p.Phe52del, PI*MMalton, or MMalton. The p.Phe76del variant has been reported in at least seven studies in 16 patients with reduced serum alpha-1 antitrypsin (AAT) concentrations and other phenotypic features consistent with alpha-1 antitrypsin deficiency, including in one in a homozygous state and in 15 in a compound heterozygous state (Sproule et al. 1983; Allen et al 1986; Curiek et al. 1989; Frazier et al. 1989; Lara et al. 2013; Suh-Lailam et al. 2014; Beletic et al 2014). The p.Phe76del variant has also been found in a heterozygous state in at least three individuals with reduced alpha-1 antitrypsin concentrations and normal pulmonary function. The variant was absent from 311 controls and is reported at a frequency of 0.00069 in the East Asian population of the Exome Aggregation Consortium. Curiel et al. (1989) demonstrated abnormal intracellular accumulation of newly synthesized AAT protein in an individual homozygous for the p.Phe76del variant, with inflammation, mild fibrosis, and intrahepatocyte AAT protein accumulation revealed on liver biopsy. Furthermore, functional analysis by retroviral gene transfer of AAT cDNA with the variant into murine cells demonstrated that abnormal intracellular accumulation of AAT protein occurred (Curiel et al 1989). Based on the collective evidence, the p.Phe76del variant is classified as pathogenic for alpha-1 antitrypsin deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Counsyl	RCV000262058	SCV000485286	pathogenic	Alpha-1-antitrypsin deficiency	2015-11-20	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000594562	SCV000704705	pathogenic	not provided	2017-12-08	criteria provided, single submitter	clinical testing
Invitae	RCV000262058	SCV000818989	pathogenic	Alpha-1-antitrypsin deficiency	2023-12-30	criteria provided, single submitter	clinical testing	This variant, c.227_229del, results in the deletion of 1 amino acid(s) of the SERPINA1 protein (p.Phe76del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs775982338, gnomAD 0.04%). This variant has been observed in individuals with alpha-1-antitrypsin deficiency (AATD) (PMID: 2788166, 3491442, 6600898, 15744045, 22291048, 24183282, 27296815, 27882547). It has also been observed to segregate with disease in related individuals. This variant is also known as PI*Mmalton or Phe52del. ClinVar contains an entry for this variant (Variation ID: 315028). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects SERPINA1 function (PMID: 2788166). For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003417992	SCV004114447	pathogenic	SERPINA1-related condition	2023-12-22	criteria provided, single submitter	clinical testing	The SERPINA1 c.227_229delTCT variant is predicted to result in an in-frame deletion (p.Phe76del). This variant, also described as p.Phe52del and the PI*Mmalton allele, has been reported in the homozygous and compound heterozygous states to be pathogenic for alpha-1-antitrypsin deficiency (Curiel et al. 1989. PubMed ID: 2788166; Fraizer et al. 1989. PubMed ID: 2786335; Rodriguez-Frias et al. 2012. PubMed ID: 22291048; Silva et al. 2016. PubMed ID: 27296815). This variant produces a poorly folded protein and is associated with an increased risk of pulmonary emphysema and liver disease (Curiel et al. 1989. PubMed ID: 2788166; Giacopuzzi et al. 2018. PubMed ID: 29882371; Silva et al. 2016. PubMed ID: 27296815). The mode of inheritance of SERPINA1-related disease is complicated by co-dominance. The PI*Mmalton allele has been detected in the heterozygous state in healthy individuals of advanced age; however, heterozygotes are at an increased risk of respiratory complications, which is elevated by cigarette smoke exposure (Aiello et al. 2020. PubMedID 32076552). A homozygous individual was reported with liver fibrosis and cirhosis, and compound heterozygosity with the Z allele was associated with chronic pulmonary obstructive disease (Joly et al. 2015. PubMed ID: 26446624). This variant is reported in 0.040% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as pathogenic.
Baylor Genetics	RCV000262058	SCV004203117	pathogenic	Alpha-1-antitrypsin deficiency	2023-10-07	criteria provided, single submitter	clinical testing
OMIM	RCV000019568	SCV000039865	other	PI M(MALTON)	2016-07-15	no assertion criteria provided	literature only
GeneReviews	RCV000262058	SCV000256614	not provided	Alpha-1-antitrypsin deficiency		no assertion provided	literature only
Department of Laboratory Medicine and Genetics, Trillium Health Partners Credit Valley Hospital	RCV000262058	SCV000608307	pathogenic	Alpha-1-antitrypsin deficiency	2014-12-08	no assertion criteria provided	curation	amino acid deletion
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000594562	SCV001978544	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000594562	SCV001980309	pathogenic	not provided		no assertion criteria provided	clinical testing