ClinVar Genomic variation as it relates to human health
NM_000187.4(HGD):c.175del (p.Ser59fs)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000187.4(HGD):c.175del (p.Ser59fs)
Variation ID: 3171 Accession: VCV000003171.19
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 3q13.33 3: 120674902 (GRCh38) [ NCBI UCSC ] 3: 120393749 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Oct 2, 2013 Aug 4, 2024 May 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000187.4:c.175del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000178.2:p.Ser59fs frameshift NM_000187.4:c.175delA MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000187.3:c.174delA NM_000187.3:c.175del NC_000003.12:g.120674903del NC_000003.11:g.120393750del NG_011957.1:g.12580del - Protein change
- S59fs
- Other names
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- Canonical SPDI
- NC_000003.12:120674901:TT:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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- Comment on variant
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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HGD | - | - |
GRCh38 GRCh37 |
535 | 560 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
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Oct 22, 2023 | RCV000003321.18 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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May 1, 2024 | RCV001169911.7 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(May 03, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: no
Allele origin:
unknown
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Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV001251859.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
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Pathogenic
(Oct 22, 2023)
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criteria provided, single submitter
Method: clinical testing
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Alkaptonuria
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001226002.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Ser59Alafs*52) in the HGD gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Ser59Alafs*52) in the HGD gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HGD are known to be pathogenic (PMID: 12501223, 19862842). This variant is present in population databases (rs587776556, gnomAD 0.08%). This premature translational stop signal has been observed in individual(s) with alkaptonuria (PMID: 10594001, 12872836, 18945288, 19862842, 25681086). It has also been observed to segregate with disease in related individuals. This variant is also known as p.R58fs. ClinVar contains an entry for this variant (Variation ID: 3171). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Aug 26, 2022)
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criteria provided, single submitter
Method: clinical testing
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Alkaptonuria
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004848738.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Ser59AlafsX52 variant in HGD has been reported in at least 7 individuals with alkaptonuria and segregated with disease in 5 affected individuals from 4 … (more)
The p.Ser59AlafsX52 variant in HGD has been reported in at least 7 individuals with alkaptonuria and segregated with disease in 5 affected individuals from 4 families (Beltran-Valero 1999 PMID: 10594001, Uyguner 2003 PMID: 12872836, Abdulrazzaq 2009 PMID: 18945288, Usher 2015 PMID:25681086, Akbaba 2020 PMID: 31927521). It has also been identified in 0.06% (3/4828) of South Asian and 0.001% (1/68026) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 3171). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 59 and leads to a premature termination codon 52 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the HGD gene is an established disease mechanism in autosomal recessive alkaptonuria. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive alkaptonuria. ACMG/AMP Criteria applied: PVS1, PP1_Strong, PM3_Strong. (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Alkaptonuria
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV005044826.2
First in ClinVar: May 26, 2024 Last updated: Jun 17, 2024 |
Comment:
The frameshift variant c.175del p.Ser59AlafsTer52 in the HGD gene has been reported previously in homozygous and compound heterozygous states in multiple individuals affected with Alkaptonuria … (more)
The frameshift variant c.175del p.Ser59AlafsTer52 in the HGD gene has been reported previously in homozygous and compound heterozygous states in multiple individuals affected with Alkaptonuria Kisa et al., 2021; Usher et al., 2015. This c.175delA has been reported as the most common variant among Alkaptonuria patients. This variant is reported with the allele frequency 0.01% in the gnomAD Exomes and novel not in any individuals in 1000 Genomes. It is submitted to ClinVar as Pathogenic Multiple submissions. This variant is predicted to cause a loss of normal protein function through protein truncation. Loss of function variants has been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Abnormality of the skin (present)
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Pathogenic
(May 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV005050738.3
First in ClinVar: Jun 17, 2024 Last updated: Aug 04, 2024 |
Comment:
HGD: PVS1, PM2, PM3
Number of individuals with the variant: 1
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Pathogenic
(Mar 09, 2016)
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criteria provided, single submitter
Method: clinical testing
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Alkaptonuria
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000485146.2
First in ClinVar: Dec 08, 2015 Last updated: Dec 24, 2022 |
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Alkaptonuria
Affected status: yes
Allele origin:
germline
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Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Accession: SCV004030498.1
First in ClinVar: Sep 03, 2023 Last updated: Sep 03, 2023 |
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Pathogenic
(Jan 01, 2003)
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no assertion criteria provided
Method: literature only
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ALKAPTONURIA
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000023479.3
First in ClinVar: Apr 04, 2013 Last updated: May 08, 2015 |
Comment on evidence:
In a single Finnish pedigree with alkaptonuria (AKU; 203500), Beltran-Valero de Bernabe et al. (1999) reported a 1-bp deletion at nucleotide 342 resulting in a … (more)
In a single Finnish pedigree with alkaptonuria (AKU; 203500), Beltran-Valero de Bernabe et al. (1999) reported a 1-bp deletion at nucleotide 342 resulting in a frameshift with translation of the first 58 amino acids of the normal HGD protein followed by 31 unrelated amino acids. See also 607474.0011 and Elcioglu et al. (2003). (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: research
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Alkaptonuria
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Department Of Human Genetics, Institute Of Clinical And Translational Research, Biomedical Research Center, Slovak Academy Of Sciences
Accession: SCV004098950.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
The variant was originally described in AKU patient in PMID:10594001. It has been submitted to the HGD gene mutation database (http://hgddatabase.cvtisr.sk/, DB-ID: AKU_00013).
Number of individuals with the variant: 131
Family history: yes
Secondary finding: no
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not provided
(-)
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no classification provided
Method: literature only
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Alkaptonuria
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV000086742.3
First in ClinVar: Oct 02, 2013 Last updated: Oct 01, 2022 |
Comment:
Frequent frameshift variant
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Alkaptonuria. | Adam MP | - | 2021 | PMID: 20301627 |
Analysis of HGD Gene Mutations in Patients with Alkaptonuria from the United Kingdom: Identification of Novel Mutations. | Usher JL | JIMD reports | 2015 | PMID: 25681086 |
Mutation spectrum of homogentisic acid oxidase (HGD) in alkaptonuria. | Vilboux T | Human mutation | 2009 | PMID: 19862842 |
R58fs mutation in the HGD gene in a family with alkaptonuria in the UAE. | Abdulrazzaq YM | Annals of human genetics | 2009 | PMID: 18945288 |
Molecular analyses of the HGO gene mutations in Turkish alkaptonuria patients suggest that the R58fs mutation originated from central Asia and was spread throughout Europe and Anatolia by human migrations. | Uyguner O | Journal of inherited metabolic disease | 2003 | PMID: 12872836 |
Alkaptonuria caused by compound heterozygote mutations. | Elçioğlu NH | Genetic counseling (Geneva, Switzerland) | 2003 | PMID: 12872815 |
Natural history of alkaptonuria. | Phornphutkul C | The New England journal of medicine | 2002 | PMID: 12501223 |
Mutational analysis of the HGO gene in Finnish alkaptonuria patients. | Beltrán-Valero de Bernabé D | Journal of medical genetics | 1999 | PMID: 10594001 |
Text-mined citations for rs397515517 ...
HelpRecord last updated Aug 04, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.
NCBI staff reviewed the sequence numbering for gene HGD reported in PubMed 9244427 to determine the location of this variant on the current reference sequence. 342delA reported on AF000573.1 can be mapped to c.175delA on transcript NM_000187.3.