NM_000190.4(HMBS):c.874C>T (p.Gln292Ter) AND not provided

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Oct 10, 2021
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:: RCV000807669.5

Allele description [Variation Report for NM_000190.4(HMBS):c.874C>T (p.Gln292Ter)]

NM_000190.4(HMBS):c.874C>T (p.Gln292Ter)

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.874C>T (p.Gln292Ter)

HGVS:

NC_000011.10:g.119092983C>T
NG_008093.1:g.13107C>T
NM_000190.4:c.874C>TMANE SELECT
NM_001024382.2:c.823C>T
NM_001258208.2:c.754C>T
NM_001258209.2:c.703C>T
NP_000181.2:p.Gln292Ter
NP_001019553.1:p.Gln275Ter
NP_001245137.1:p.Gln252Ter
NP_001245138.1:p.Gln235Ter
LRG_1076t1:c.874C>T
LRG_1076t2:c.823C>T
LRG_1076:g.13107C>T
LRG_1076p1:p.Gln292Ter
LRG_1076p2:p.Gln275Ter
NC_000011.9:g.118963693C>T
NM_000190.3:c.874C>T
NM_001258208.1:c.754C>T

Protein change:

Q235*

Links:

dbSNP: rs1592220915

NCBI 1000 Genomes Browser:

rs1592220915

Molecular consequence:

NM_000190.4:c.874C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001024382.2:c.823C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001258208.2:c.754C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001258209.2:c.703C>T - nonsense - [Sequence Ontology: SO:0001587]

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
SCV000947735	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 10, 2021)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 8168829, 9463797, 9702975, 10944860, 19138865, 10782018, 11831862, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000947735

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 10, 2021)

germline

clinical testing

PubMed (8)
[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 caused by a single base insertion of C in exon 15 of the porphobilinogen deaminase gene that results in a frame shift and premature stopping of translation.

Daimon M, Yamatani K, Igarashi M, Fukase N, Morita Y, Ogawa A, Tominaga M, Sasaki H.

Hum Genet. 1994 May;93(5):533-7.

PubMed [citation]

PMID:: 8168829

Identification of two novel mutations in the hydroxymethylbilane synthase gene in three patients from two unrelated families with acute intermittent porphyria.

Ong PM, Lanyon WG, Hift RJ, Halkett J, Cramp CE, Moore MR, Connor JM.

Hum Hered. 1998 Jan-Feb;48(1):24-9.

PubMed [citation]

PMID:: 9463797

See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000947735.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the HMBS protein. Other variant(s) that disrupt this region (p.Gln328Valfs*30, p.Leu329Phefs*30, p.Gly335Alafs*9, and p.Arg355Profs*4) have been observed in individuals with HMBS-related conditions (PMID: 8168829, 9463797, 9702975, 10944860, 19138865). This suggests that this may be a clinically significant region of the protein. ClinVar contains an entry for this variant (Variation ID: 652166). This premature translational stop signal has been observed in individuals with acute intermittent porphyria (PMID: 10782018, 11831862). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln292*) in the HMBS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 70 amino acid(s) of the HMBS protein.

#	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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