NM_000187.4(HGD):c.1006+2T>A AND Alkaptonuria

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Apr 21, 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:: RCV001381505.7

Allele description [Variation Report for NM_000187.4(HGD):c.1006+2T>A]

NM_000187.4(HGD):c.1006+2T>A

Gene:

HGD:homogentisate 1,2-dioxygenase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3q13.33

Genomic location:

Preferred name:

NM_000187.4(HGD):c.1006+2T>A

HGVS:

NC_000003.12:g.120638453A>T
NG_011957.1:g.49029T>A
NM_000187.4:c.1006+2T>AMANE SELECT
NC_000003.11:g.120357300A>T

Links:

dbSNP: rs1320184173

NCBI 1000 Genomes Browser:

rs1320184173

Molecular consequence:

NM_000187.4:c.1006+2T>A - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:: Alkaptonuria (AKU)
Synonyms:: Alcaptonuria; Ochronosis, hereditary; Homogentisic acid oxidase deficiency; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0008753; MedGen: C0002066; Orphanet: 56; OMIM: 203500

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001579933	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 21, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 16199547, 12501223, 19862842, 28492532
SCV004101008	Department Of Human Genetics, Institute Of Clinical And Translational Research, Biomedical Research Center, Slovak Academy Of Sciences	no assertion criteria provided	Pathogenic	germline	research	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001579933

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Apr 21, 2021)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV004101008

Department Of Human Genetics, Institute Of Clinical And Translational Research, Biomedical Research Center, Slovak Academy Of Sciences

no assertion criteria provided

Pathogenic

germline

research

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	1	not provided	not provided	yes	research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]

PMID:: 16199547
PMCID:: PMC1735933

Natural history of alkaptonuria.

Phornphutkul C, Introne WJ, Perry MB, Bernardini I, Murphey MD, Fitzpatrick DL, Anderson PD, Huizing M, Anikster Y, Gerber LH, Gahl WA.

N Engl J Med. 2002 Dec 26;347(26):2111-21.

PubMed [citation]

PMID:: 12501223

See all PubMed Citations (4)

Details of each submission

From Invitae, SCV001579933.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in HGD are known to be pathogenic (PMID: 12501223, 19862842). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in individual(s) with alkaptonuria (PMID: 19862842). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 12 of the HGD gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.

#	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

From Department Of Human Genetics, Institute Of Clinical And Translational Research, Biomedical Research Center, Slovak Academy Of Sciences, SCV004101008.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	yes	research	PubMed (1)

Description

The variant was originally described in AKU patient in PMID:19862842. It has been submitted to the HGD gene mutation database (http://hgddatabase.cvtisr.sk/, DB-ID: AKU_00089).

#	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		1	not provided	1	not provided

Last Updated: Feb 20, 2024

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