ClinVar Miner

Submissions for variant NM_000190.4(HMBS):c.500G>A (p.Arg167Gln) (rs118204095)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000520560 SCV000616739 likely pathogenic not provided 2018-09-26 criteria provided, single submitter clinical testing The R167Q variant in the HMBS gene has been reported previously in the heterozygous state in association with acute intermittent porphyria (Delfau et al., 1990). R167Q has also been reported in the compound heterozygous state with another HMBS variant in affected individuals from two families with spasticity, ataxia, neuropathy, and abnormal head imaging findings (Llewellyn et al., 1992; Kevelam et al., 2016). Functional studies demonstrate that the R167Q variant results in a dramatic reduction in enzymatic activity to approximately 1% of wild type levels (Delfau et al., 1990; Chen et al., 2016). The R167Q variant is observed in 8/72,186 (0.01%) alleles from individuals of non-Finnish European background in large population cohorts (Lek et al., 2016). The R167Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. We interpret R167Q as a likely pathogenic variant.
Mount Sinai Diagnostic Laboratory,Icahn School of Medicine at Mount Sinai RCV000001511 SCV001132052 pathogenic Acute intermittent porphyria criteria provided, single submitter research
Invitae RCV000520560 SCV001220631 pathogenic not provided 2019-03-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 167 of the HMBS protein (p.Arg167Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs118204095, ExAC 0.04%). This variant has been observed in individuals affected with acute intermittent porphyria (PMID: 2243128, 7962538, 12372055, 15003823, 9199558) and in individuals from two families affected with this condition who also had another variant in the HBMS gene (PMID: 27558376, 1577472). ClinVar contains an entry for this variant (Variation ID: 1446). Experimental studies have shown that this missense change abrogates HMBS enzyme activity and reduces enzyme stability (PMID: 27539938, 2243128, 12773194). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. The p.Arg167 amino acid residue in HMBS has been determined to be clinically significant (PMID: 27539938, 11055586, 15643298, 23815679, 15003823, 7962538, 12372055). This suggests that variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000001511 SCV000021666 pathogenic Acute intermittent porphyria 1992-04-01 no assertion criteria provided literature only
CSER _CC_NCGL, University of Washington RCV000001511 SCV000190221 uncertain significance Acute intermittent porphyria 2014-06-01 no assertion criteria provided research

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