NM_000190.4(HMBS):c.625G>A (p.Glu209Lys) AND not provided

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jan 31, 2023
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:: RCV003062464.3

Allele description [Variation Report for NM_000190.4(HMBS):c.625G>A (p.Glu209Lys)]

NM_000190.4(HMBS):c.625G>A (p.Glu209Lys)

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.625G>A (p.Glu209Lys)

HGVS:

NC_000011.10:g.119092137G>A
NG_008093.1:g.12261G>A
NM_000190.4:c.625G>AMANE SELECT
NM_001024382.2:c.574G>A
NM_001258208.2:c.625G>A
NM_001258209.2:c.574G>A
NP_000181.2:p.Glu209Lys
NP_001019553.1:p.Glu192Lys
NP_001245137.1:p.Glu209Lys
NP_001245138.1:p.Glu192Lys
LRG_1076t1:c.625G>A
LRG_1076t2:c.574G>A
LRG_1076:g.12261G>A
LRG_1076p1:p.Glu209Lys
LRG_1076p2:p.Glu192Lys
NC_000011.9:g.118962847G>A

Protein change:

E192K

Molecular consequence:

NM_000190.4:c.625G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001024382.2:c.574G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258208.2:c.625G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258209.2:c.574G>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
SCV003440956	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 31, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 9199558, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003440956

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 31, 2023)

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

Molecular epidemiology and diagnosis of PBG deaminase gene defects in acute intermittent porphyria.

Puy H, Deybach JC, Lamoril J, Robreau AM, Da Silva V, Gouya L, Grandchamp B, Nordmann Y.

Am J Hum Genet. 1997 Jun;60(6):1373-83.

PubMed [citation]

PMID:: 9199558
PMCID:: PMC1716106

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 Labcorp Genetics (formerly Invitae), Labcorp, SCV003440956.2

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

Description

This variant is present in population databases (no rsID available, gnomAD 0.0009%). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. This missense change has been observed in individual(s) with acute intermittent porphyria (PMID: 9199558). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 209 of the HMBS protein (p.Glu209Lys).

#	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 29, 2024

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