ClinVar Miner

Submissions for variant NM_000295.5(SERPINA1):c.646+1G>T

gnomAD frequency: 0.00001  dbSNP: rs751235320
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000593270 SCV007537716 likely pathogenic not provided 2025-09-25 criteria provided, single submitter clinical testing Reported as a single heterozygous finding in a proband with emphysema, asthma, bronchitis and a history of smoking (PMID: 8364536); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 8364536, 36451132, 29625052, 37277845)
Baylor Genetics RCV000169461 SCV004203125 likely pathogenic Alpha-1-antitrypsin deficiency 2023-07-19 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000169461 SCV002245454 pathogenic Alpha-1-antitrypsin deficiency 2025-06-22 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 2 of the SERPINA1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SERPINA1 are known to be pathogenic (PMID: 25425243). This variant is present in population databases (rs751235320, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with SERPINA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 189064). Studies have shown that disruption of this splice site alters SERPINA1 gene expression (PMID: 8364536). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Eurofins Ntd Llc (ga) RCV000593270 SCV000706472 likely pathogenic not provided 2017-02-21 criteria provided, single submitter clinical testing
Dr. Peter K. Rogan Lab, Western University RCV005889647 SCV006837261 not provided Hepatocellular carcinoma no classification provided in vitro
Department of Laboratory Medicine and Genetics, Trillium Health Partners Credit Valley Hospital RCV000169461 SCV000608321 pathogenic Alpha-1-antitrypsin deficiency 2014-12-08 no assertion criteria provided curation
Counsyl RCV000169461 SCV000220891 likely pathogenic Alpha-1-antitrypsin deficiency 2014-11-14 no assertion criteria provided literature only This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.
OMIM RCV000019606 SCV000039904 other PI NULL(WEST) 2016-07-15 no assertion criteria provided literature only

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