Non-acute porphyrias

Gene: HMBS

Comment on mode of inheritance: After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains Green. GMS reviewers note that this panel is used for biochemically undiagnosed porphyria - acute and non-acute. The MOI was updated to BOTH monoallelic and biallelic, autosomal or pseudoautosomal, as suggested by the NHS Genomic Medicine Service.

Created: 20 Jan 2026, 11:23 a.m. | Last Modified: 20 Jan 2026, 11:23 a.m.

Panel Version: 1.34

The to_be_confirmed_NHSE tag has been added, as further NHSE review is required before changing the mode of inheritance.

Created: 12 Dec 2025, 10:47 a.m. | Last Modified: 12 Dec 2025, 10:47 a.m.

Panel Version: 1.33

After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains Green. GMS reviewers note that this panel is used for biochemically undiagnosed porphyria.

Created: 11 Dec 2025, 4:38 p.m. | Last Modified: 11 Dec 2025, 4:38 p.m.

Panel Version: 1.33

Tagging for GMS expert review to determine whether this gene should be demoted from green to red, given the phenotype typically caused by heterozygous variants consists of acute intermittent porphyria which is outside the scope of this panel. On the other hand, recessive phenotypes (OMIM:620704, OMIM:620711) are more severe and possibly more relevant to the panel but this should be reviewed by the expert group.

Therefore, if recessive phenotypes are determine as relevant, the gene should remain green and the MOI changed to BIALLELIC, autosomal or pseudoautosomal.

Created: 2 Jul 2025, 9:33 a.m. | Last Modified: 2 Jul 2025, 9:33 a.m.

Panel Version: 1.26

Red List (low evidence)

Because this panel is focused on non-acute porphyrias, Sharon Whatley (International Porphyria Network) has rated HMBS red on this panel. If the rare biallelic pathogenic HMBS variants that Sharon Whatley mentions in her review are to be analyzed, the mode of inheritance should be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.

Created: 24 Apr 2025, 12:46 p.m. | Last Modified: 24 Apr 2025, 12:46 p.m.

Panel Version: 1.26

Red List (low evidence)

Update 23/10/2025:
The relevance of the biallelic form of HMBS was discussed at the IPNET (International Porphyria Network) laboratory working group. According to the IPNET definition of acute intermittent porphyria, the biallelic form also meets the definition of an acute porphyria rather than the non-acute. In a clinical context these patients would be investigated using a symptomatic panel. We would recommend that HMBS is not part of the non-acute porphyria panel.

Created: 23 Oct 2025, 7:55 a.m. | Last Modified: 23 Oct 2025, 7:55 a.m.

Panel Version: 1.29

PMID: 37540847 Dickey reports that acute intermittent porphyria is an autosomal dominant disease caused by a pathogenic variant in the HMBS gene. The clinical characteristics are acute neurovisceral attacks characterized by severe abdominal pain and neuropsychiatric symptoms. This is an acute disorder and should not be part of a non-acute porphyria panel.
The only area of confusion may be the very rare biallelic inheritance of HMBS pathogenic variants. PMID: 14262853 De Villeneuve, 1577472 Llewellyn, 15534187 Solis, 14970743 Hessels, 27558376 Kevelam, 31153822 Dixon and 34089223 Stutterd. This has been reported in six children (5 families) five children with severe progressive neurological disease and in six adults (3 families) with leukoencephalopathy but no confirmed acute attacks.
Careful consideration should be given to the reporting of a single pathogenic variant as an incidental finding in the HMBS gene, due to its low clinical penetrance.

Created: 4 Apr 2025, 3:09 p.m. | Last Modified: 4 Apr 2025, 3:09 p.m.

Panel Version: 1.24

Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

Phenotypes
176000; 620711; 620704

Publications

• 37540847
• 14262853
• 1577472
• 15534187
• 14970743
• 27558376
• 31153822
• 34089223

Green List (high evidence)

Comment when marking as ready: As discussed in the GMS Gastrohepatology Specialist Test Group webex call 14th Jan 2019: The Specialist Test Group agreed that there is enough evidence to rate this gene green.

Created: 24 Jan 2019, 4:21 p.m.

Initial gene list and info collated by Miranda Durkie Sheffield Diagnostic Genetics Service December 2018 on behalf of the GMS Gastrohepatology specialist test group. Gene Symbol submitted: HMBS; Suggested intial gene rating: Green; Evidence for inclusion: none given; Evidence for exclusion: none given; Technical notes (e.g. non-coding/CNV mutations requiring coverage?): none given

Created: 7 Jan 2019, 3:53 p.m.

Green List (high evidence)

HMBS is the third enzyme of the biosynthetic pathway leading to the production of heme. >3 unrelated cases from multiple populations providing gene:disease association. Plus animal model.

Created: 23 Feb 2017, 5:14 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Porphyria, acute intermittent, 176000; Porphyria, acute intermittent, nonerythroid variant, 176000

Publications

• 2511016
• 1714233