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

gnomAD frequency: 0.00006  dbSNP: rs118204095

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000520560	SCV000616739	likely pathogenic	not provided	2024-06-13	criteria provided, single submitter	clinical testing	Reported in the compound heterozygous state with another HMBS variant in individuals from 2 families with spasticity, ataxia, neuropathy, and abnormal head imaging (PMID: 1577472, 27558376); Published functional studies demonstrate dramatic reduction in enzymatic activity to approximately 1% of wild type levels (PMID: 27539938, 2243128); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis supports that this missense variant has a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 19207107, 25637381, 2243128, 27558376, 29360981, 15534187, 32197664, 12773194, 12699244, 30615115, 7962538, 15003823, 9199558, 26075277, 12372055, 25016127, 34791078, 35327450, 34308104, 34089223, 27539938, 31153822, 1577472)
Mount Sinai Diagnostic Laboratory, Icahn School of Medicine at Mount Sinai	RCV000001511	SCV001132052	pathogenic	Acute intermittent porphyria		criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000520560	SCV001220631	pathogenic	not provided	2024-12-26	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 167 of the HMBS protein (p.Arg167Gln). This variant is present in population databases (rs118204095, gnomAD 0.01%). This missense change has been observed in individuals with autosomal dominant acute intermittent porphyria (PMID: 2243128, 7962538, 9199558, 12372055, 15003823). ClinVar contains an entry for this variant (Variation ID: 1446). 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: 2243128, 12773194, 27539938). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Arg167 amino acid residue in HMBS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7962538, 11055586, 12372055, 15003823, 15643298, 23815679, 27539938). 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.
Centogene AG - the Rare Disease Company	RCV000001511	SCV002059538	likely pathogenic	Acute intermittent porphyria	2018-02-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000001511	SCV004099797	pathogenic	Acute intermittent porphyria	2023-09-13	criteria provided, single submitter	clinical testing	Variant summary: HMBS c.500G>A (p.Arg167Gln) results in a conservative amino acid change located in the N-terminal domain (IPR022417) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. In addition, this variant disrupts the second nucleotide of exon 9, and therefore can affect splicing. Several computational tools predict a significant impact on normal splicing: Two predict the variant weakens a 3' acceptor site. Two predict the variant creates a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.5e-05 in 156322 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.500G>A has been reported in the literature in multiple individuals affected with Acute Intermittent Porphyria (e.g., Delfau_1990, Chen_1994, vonBrasch_2004, Floderus_2002). These data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function, finding that the variant results in <10% of specific activity relative to wild type (e.g, Delfau_1990, Gill_2009). The following publications have been ascertained in the context of this evaluation (PMID: 7962538, 2243128, 12372055, 19207107, 15003823). Three submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000520560	SCV004226624	likely pathogenic	not provided	2022-10-07	criteria provided, single submitter	clinical testing	PP3, PM2, PM5, PS3
OMIM	RCV000001511	SCV000021666	pathogenic	Acute intermittent porphyria	2004-11-01	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
GenomeConnect - Invitae Patient Insights Network	RCV000001511	SCV001749825	not provided	Acute intermittent porphyria		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 03-26-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
OMIM	RCV003764509	SCV004697358	pathogenic	Encephalopathy, porphyria-related	2004-11-01	no assertion criteria provided	literature only
OMIM	RCV003764510	SCV004697359	pathogenic	Leukoencephalopathy, porphyria-related	2004-11-01	no assertion criteria provided	literature only