NM_000190.4(HMBS):c.724G>A (p.Glu242Lys) AND not provided

This record was updated by the submitter. Please see the current version.

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Oct 2, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001943901.4

Allele description

NM_000190.4(HMBS):c.724G>A (p.Glu242Lys)

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.724G>A (p.Glu242Lys)

HGVS:

NC_000011.10:g.119092476G>A
NG_008093.1:g.12600G>A
NM_000190.4:c.724G>AMANE SELECT
NM_001024382.2:c.673G>A
NM_001258208.2:c.652-282G>A
NM_001258209.2:c.601-282G>A
NP_000181.2:p.Glu242Lys
NP_001019553.1:p.Glu225Lys
LRG_1076t1:c.724G>A
LRG_1076t2:c.673G>A
LRG_1076:g.12600G>A
LRG_1076p1:p.Glu242Lys
LRG_1076p2:p.Glu225Lys
NC_000011.9:g.118963186G>A

Protein change:

E225K

Links:

dbSNP: rs761810461

NCBI 1000 Genomes Browser:

rs761810461

Molecular consequence:

NM_001258208.2:c.652-282G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001258209.2:c.601-282G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000190.4:c.724G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001024382.2:c.673G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002192750	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 2, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 27539938, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002192750

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 2, 2022)

germline

clinical testing

PubMed (2)
[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

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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV002192750.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 242 of the HMBS protein (p.Glu242Lys). This variant is present in population databases (rs761810461, gnomAD 0.006%). 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: 1421852). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on HMBS function (PMID: 27539938). 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: Sep 1, 2024

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