NM_000190.4(HMBS):c.737G>A (p.Arg246His) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Dec 19, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000521233.6

Allele description [Variation Report for NM_000190.4(HMBS):c.737G>A (p.Arg246His)]

NM_000190.4(HMBS):c.737G>A (p.Arg246His)

Gene:

HMBS:hydroxymethylbilane synthase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11q23.3

Genomic location:

Preferred name:

NM_000190.4(HMBS):c.737G>A (p.Arg246His)

HGVS:

NC_000011.10:g.119092489G>A
NG_008093.1:g.12613G>A
NM_000190.4:c.737G>AMANE SELECT
NM_001024382.2:c.686G>A
NM_001258208.2:c.652-269G>A
NM_001258209.2:c.601-269G>A
NP_000181.2:p.Arg246His
NP_001019553.1:p.Arg229His
LRG_1076t1:c.737G>A
LRG_1076t2:c.686G>A
LRG_1076:g.12613G>A
LRG_1076p1:p.Arg246His
LRG_1076p2:p.Arg229His
NC_000011.9:g.118963199G>A
NM_000190.3:c.737G>A

Protein change:

R229H

Links:

dbSNP: rs201909197

NCBI 1000 Genomes Browser:

rs201909197

Molecular consequence:

NM_001258208.2:c.652-269G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001258209.2:c.601-269G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000190.4:c.737G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001024382.2:c.686G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

Clear Turn Off Turn On

HIC1 HIC ZBTB transcriptional repressor 1 [Homo sapiens]
HIC1 HIC ZBTB transcriptional repressor 1 [Homo sapiens]
Gene ID:3090

Gene
Gene Links for GEO Profiles (Select 126740370) (1)
Gene
Chromosome neighbors for GEO Profiles (Select 99093409) (20)
GEO Profiles

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000621338	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Uncertain significance (Oct 9, 2017)	germline	clinical testing	Citation Link,
SCV002165367	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 19, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 27539938, 29360981, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000621338

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Uncertain significance
(Oct 9, 2017)

germline

clinical testing

Citation Link,

SCV002165367

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 19, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Acute Intermittent Porphyria: Predicted Pathogenicity of HMBS Variants Indicates Extremely Low Penetrance of the Autosomal Dominant Disease.

Chen B, Solis-Villa C, Hakenberg J, Qiao W, Srinivasan RR, Yasuda M, Balwani M, Doheny D, Peter I, Chen R, Desnick RJ.

Hum Mutat. 2016 Nov;37(11):1215-1222. doi: 10.1002/humu.23067. Epub 2016 Sep 5.

PubMed [citation]

PMID:: 27539938
PMCID:: PMC5063710

From a dominant to an oligogenic model of inheritance with environmental modifiers in acute intermittent porphyria.

Lenglet H, Schmitt C, Grange T, Manceau H, Karboul N, Bouchet-Crivat F, Robreau AM, Nicolas G, Lamoril J, Simonin S, Mirmiran A, Karim Z, Casalino E, Deybach JC, Puy H, Peoc'h K, Gouya L.

Hum Mol Genet. 2018 Apr 1;27(7):1164-1173. doi: 10.1093/hmg/ddy030.

PubMed [citation]

PMID:: 29360981

See all PubMed Citations (3)

Details of each submission

From GeneDx, SCV000621338.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The R246H variant in the HMBS gene has been reported as a predicted benign variant based on ambiguous in silico predictions and in vitro expression activity (Chen wt al., 2016). The R246H variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The R246H variant is a conservative amino acid substitution, which at a position that is not conserved. In silico analysis at GeneDx predicts this variant is probably damaging to the protein structure/function. We interpret R246H as a variant of uncertain significance

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV002165367.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 246 of the HMBS protein (p.Arg246His). This variant is present in population databases (rs201909197, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with HMBS-related conditions. ClinVar contains an entry for this variant (Variation ID: 452525). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt HMBS protein function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on HMBS function (PMID: 27539938, 29360981). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 28, 2024

ClinVar

Relating variation to medicine