The heterozygous variant c.347T>C (p.Leu116Pro) has been identified in compound heterozygous state with c.518T>C (p.Leu173Pro) in a proband with alkaptonuria. This variant is present in exon 6 is in a mutational hotspot region where 10 pathogenic variants have been reported so far (PM1_moderate). In this gene, 79 pathogenic missense variants (PP2_supporting) have been reported. Variant has been found 0.0044% in gnomAD (aggregated) (PM2_Moderate). This variant has been previously reported: PMID:25681086 (PP5_strong).
ClinVar Genomic variation as it relates to human health
NM_000187.4(HGD):c.347T>C (p.Leu116Pro)
Germline
Classification
Help
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.
(5)
Help
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.
Pathogenic/Likely pathogenic
5
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000187.4(HGD):c.347T>C (p.Leu116Pro)
Variation ID: 554869 Accession: VCV000554869.9
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3q13.33 3: 120650861 (GRCh38) [ NCBI UCSC ] 3: 120369708 (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 Aug 5, 2018 Oct 13, 2024 Sep 22, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000187.4:c.347T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000178.2:p.Leu116Pro missense NC_000003.12:g.120650861A>G NC_000003.11:g.120369708A>G NG_011957.1:g.36621T>C - Protein change
- L116P
- Other names
- -
- Canonical SPDI
- NC_000003.12:120650860:A:G
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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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0.00020 (G)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00000
Exome Aggregation Consortium (ExAC) 0.00004
The Genome Aggregation Database (gnomAD), exomes 0.00004
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
- Links
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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. |
|||
| 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
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Sep 22, 2024 | RCV000670576.11 |
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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|---|---|---|---|---|---|
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Pathogenic
(Jun 24, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Alkaptonuria
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
inherited
|
Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital
Accession: SCV003935138.1
First in ClinVar: Jul 01, 2023 Last updated: Jul 01, 2023 |
Comment:
The heterozygous variant c.347T>C (p.Leu116Pro) has been identified in compound heterozygous state with c.518T>C (p.Leu173Pro) in a proband with alkaptonuria. This variant is present in … (more)
The heterozygous variant c.347T>C (p.Leu116Pro) has been identified in compound heterozygous state with c.518T>C (p.Leu173Pro) in a proband with alkaptonuria. This variant is present in exon 6 is in a mutational hotspot region where 10 pathogenic variants have been reported so far (PM1_moderate). In this gene, 79 pathogenic missense variants (PP2_supporting) have been reported. Variant has been found 0.0044% in gnomAD (aggregated) (PM2_Moderate). This variant has been previously reported: PMID:25681086 (PP5_strong). (less)
Age: 0-9 years
Sex: female
Ethnicity/Population group: South East Asian
Geographic origin: India
|
|
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Likely pathogenic
(Oct 24, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Alkaptonuria
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002279687.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 116 of the HGD protein (p.Leu116Pro). … (more)
This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 116 of the HGD protein (p.Leu116Pro). This variant is present in population databases (rs569846003, gnomAD 0.04%). This missense change has been observed in individual(s) with alkaptonuria (PMID: 23430897, 25681086, 32212000). ClinVar contains an entry for this variant (Variation ID: 554869). 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 expected to disrupt HGD protein function with a positive predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
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Likely pathogenic
(Sep 22, 2024)
|
criteria provided, single submitter
Method: clinical testing
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Alkaptonuria
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV005374474.1
First in ClinVar: Oct 13, 2024 Last updated: Oct 13, 2024 |
|
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Pathogenic
(-)
|
no assertion criteria provided
Method: research
|
Alkaptonuria
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Department Of Human Genetics, Institute Of Clinical And Translational Research, Biomedical Research Center, Slovak Academy Of Sciences
Accession: SCV004098946.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
The variant was described in AKU patient in PMID:23430897. It has been submitted to the HGD gene mutation database (http://hgddatabase.cvtisr.sk/, DB-ID: AKU_00026).
Number of individuals with the variant: 7
Family history: yes
Secondary finding: no
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Uncertain significance
(Nov 14, 2017)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Older and outlier claim with insufficient supporting evidence
Source: ClinGen
|
Alkaptonuria
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000795445.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
|
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| Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more | |||||
Comment:
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 116 of the HGD protein (p.Leu116Pro). This variant is present in population databases (rs569846003, gnomAD 0.04%). This missense change has been observed in individual(s) with alkaptonuria (PMID: 23430897, 25681086, 32212000). ClinVar contains an entry for this variant (Variation ID: 554869). 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 expected to disrupt HGD protein function with a positive predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Comment:
The variant was described in AKU patient in PMID:23430897. It has been submitted to the HGD gene mutation database (http://hgddatabase.cvtisr.sk/, DB-ID: AKU_00026).
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. |
Comment:
The heterozygous variant c.347T>C (p.Leu116Pro) has been identified in compound heterozygous state with c.518T>C (p.Leu173Pro) in a proband with alkaptonuria. This variant is present in exon 6 is in a mutational hotspot region where 10 pathogenic variants have been reported so far (PM1_moderate). In this gene, 79 pathogenic missense variants (PP2_supporting) have been reported. Variant has been found 0.0044% in gnomAD (aggregated) (PM2_Moderate). This variant has been previously reported: PMID:25681086 (PP5_strong).
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 116 of the HGD protein (p.Leu116Pro). This variant is present in population databases (rs569846003, gnomAD 0.04%). This missense change has been observed in individual(s) with alkaptonuria (PMID: 23430897, 25681086, 32212000). ClinVar contains an entry for this variant (Variation ID: 554869). 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 expected to disrupt HGD protein function with a positive predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Comment:
The variant was described in AKU patient in PMID:23430897. It has been submitted to the HGD gene mutation database (http://hgddatabase.cvtisr.sk/, DB-ID: AKU_00026).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Founder effects of the homogentisate 1,2-dioxygenase (HGD) gene in a gypsy population and mutation spectrum in the gene among alkaptonuria patients from India. | Danda S | Clinical rheumatology | 2020 | PMID: 32212000 |
| Analysis of HGD Gene Mutations in Patients with Alkaptonuria from the United Kingdom: Identification of Novel Mutations. | Usher JL | JIMD reports | 2015 | PMID: 25681086 |
| Identification of 11 Novel Homogentisate 1,2 Dioxygenase Variants in Alkaptonuria Patients and Establishment of a Novel LOVD-Based HGD Mutation Database. | Zatkova A | JIMD reports | 2012 | PMID: 23430897 |
Text-mined citations for rs569846003 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Oct 20, 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.