Submissions for variant NM_000190.4(HMBS):c.346C>T (p.Arg116Trp)

gnomAD frequency: 0.00001  dbSNP: rs118204094

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001212053	SCV001383626	pathogenic	not provided	2024-01-20	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 116 of the HMBS protein (p.Arg116Trp). This variant is present in population databases (rs118204094, gnomAD 0.0009%). This missense change has been observed in individual(s) with acute intermittent porphyria (AIP) (PMID: 8096492, 19656453, 23815679). It is commonly reported in individuals of Dutch ancestry (PMID: 19656453). ClinVar contains an entry for this variant (Variation ID: 1445). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects HMBS function (PMID: 9281416, 23815679). This variant disrupts the p.Arg116 amino acid residue in HMBS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8081367). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001212053	SCV002569876	pathogenic	not provided	2022-02-18	criteria provided, single submitter	clinical testing	Published functional studies demonstrate R116W abolishes enzymatic activity in vitro which is likely due to severe conformational instability of the variant (Bustad et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29360981, 9281416, 14757946, 23815679, 19656453, 27507172, 8096492)
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000001510	SCV002575020	pathogenic	Acute intermittent porphyria	2022-09-26	criteria provided, single submitter	research	PS3_Moderate, PS4, PM2_Supporting, PP1_Strong, PP3
Neuberg Centre For Genomic Medicine, NCGM	RCV000001510	SCV004047777	pathogenic	Acute intermittent porphyria		criteria provided, single submitter	clinical testing	The c.346C>T (p.Arg116Trp) variant in HMBS gene has been observed in several families affected with acute intermittent porphyria (Bustad et al., 2013; de Rooij et al., 2009) and has been described as a founder mutation in the Dutch population (de Rooij et al., 2009). This variant has been reported to affect HMBS protein function (Bustad et al., 2013). This variant is reported with the allele frequency (0.0003%) in the gnomAD and novel in 1000 genome database. This variant has been reported to the ClinVar database as Pathogenic. The amino acid Arg at position 116 is changed to a Trp changing protein sequence and it might alter its composition and physicochemical properties. The amino acid change p.Arg116Trp in HMBS is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV001212053	SCV004226622	pathogenic	not provided	2022-06-24	criteria provided, single submitter	clinical testing	PP3, PP4, PS3, PS4
OMIM	RCV000001510	SCV000021665	pathogenic	Acute intermittent porphyria	1993-03-01	no assertion criteria provided	literature only