NM_000190.4(HMBS):c.770dup (p.Glu258fs) AND not provided

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jul 30, 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:: RCV003062466.3

Allele description [Variation Report for NM_000190.4(HMBS):c.770dup (p.Glu258fs)]

NM_000190.4(HMBS):c.770dup (p.Glu258fs)

Gene:

HMBS:hydroxymethylbilane synthase [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

11q23.3

Genomic location:

Preferred name:

NM_000190.4(HMBS):c.770dup (p.Glu258fs)

HGVS:

NC_000011.10:g.119092522dup
NG_008093.1:g.12646dup
NM_000190.4:c.770dupMANE SELECT
NM_001024382.2:c.719dup
NM_001258208.2:c.652-236dup
NM_001258209.2:c.601-236dup
NP_000181.2:p.Glu258fs
NP_001019553.1:p.Glu241fs
LRG_1076t1:c.770dup
LRG_1076t2:c.719dup
LRG_1076:g.12646dup
LRG_1076p1:p.Glu258fs
LRG_1076p2:p.Glu241fs
NC_000011.9:g.118963231_118963232insT
NC_000011.9:g.118963232dup

Protein change:

E241fs

Molecular consequence:

NM_000190.4:c.770dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001024382.2:c.719dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001258208.2:c.652-236dup - intron variant - [Sequence Ontology: SO:0001627]
NM_001258209.2:c.601-236dup - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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alpha-L-arabinofuranosidase [Paenibacillus odorifer]
alpha-L-arabinofuranosidase [Paenibacillus odorifer]
gi|1403855663|gnl|PRJNA390216|CD191 0|gb|AWV33076.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003440953	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 30, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 8684377, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003440953

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 30, 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

Detection of four mutations in six unrelated South African patients with acute intermittent porphyria.

Ong PM, Lanyon WG, Hift RJ, Halkett J, Moore MR, Mgone CS, Connor JM.

Mol Cell Probes. 1996 Feb;10(1):57-61.

PubMed [citation]

PMID:: 8684377

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, SCV003440953.2

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

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the HMBS protein in which other variant(s) (p.Leu341Cysfs*3) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This premature translational stop signal has been observed in individual(s) with acute intermittent porphyria (PMID: 8684377). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu258Glyfs*33) in the HMBS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 104 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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