ClinVar Miner

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

dbSNP: rs775982338
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Total submissions: 9
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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 2021-11-26 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.
OMIM RCV000019568 SCV000039865 other PI M(MALTON) 2016-07-15 no assertion criteria provided literature only
GeneReviews RCV000262058 SCV000256614 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 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

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