ClinVar Miner

Submissions for variant NM_000190.4(HMBS):c.772-2A>G

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Molecular Genetics, Royal Melbourne Hospital RCV003994651 SCV004812427 pathogenic Acute intermittent porphyria 2022-08-12 criteria provided, single submitter clinical testing This sequence change in HMBS occurs within the canonical splice acceptor site (- 2) of intron 11. It is predicted to cause cryptic acceptor site activation in intron 11 leading to 104 bp intron inclusion, resulting in a frameshift leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (ClinGen Dosage Sensitivity). This variant is absent from gnomAD v2.1 and v3.1. To our knowledge, this variant has not been reported in the literature in any individuals with HMBS-related disease. At least one patient with this variant displayed an increased concentration of porphobilinogen in urine on biochemical testing, which is highly specific for acute intermittent porphyria (Royal Melbourne Hospital). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM2_Supporting, PP4.

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