ClinVar Genomic variation as it relates to human health
NM_005340.7(HINT1):c.110G>C (p.Arg37Pro)
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_005340.7(HINT1):c.110G>C (p.Arg37Pro)
Variation ID: 37312 Accession: VCV000037312.66
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5q23.3 5: 131165096 (GRCh38) [ NCBI UCSC ] 5: 130500789 (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 11, 2015 Aug 4, 2024 Jan 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_005340.7:c.110G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005331.1:p.Arg37Pro missense NM_005340.5:c.110G>C NR_024610.3:n.161G>C non-coding transcript variant NR_024611.3:n.161G>C non-coding transcript variant NR_073488.2:n.161G>C non-coding transcript variant NR_134494.2:n.161G>C non-coding transcript variant NR_134495.2:n.161G>C non-coding transcript variant NC_000005.10:g.131165096C>G NC_000005.9:g.130500789C>G NG_032998.1:g.5253G>C P49773:p.Arg37Pro - Protein change
- R37P
- Other names
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- Canonical SPDI
- NC_000005.10:131165095:C: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) 0.00010
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
Exome Aggregation Consortium (ExAC) 0.00025
The Genome Aggregation Database (gnomAD), exomes 0.00026
The Genome Aggregation Database (gnomAD) 0.00064
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
Help
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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HINT1 | - | - |
GRCh38 GRCh37 |
122 | 148 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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. |
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Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
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Dec 29, 2023 | RCV000030852.22 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 1, 2024 | RCV000235535.25 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 10, 2021 | RCV001814014.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 23, 2022 | RCV002426529.3 |
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
(Nov 14, 2023)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive axonal neuropathy with neuromyotonia
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV004101800.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Clinical Features:
Polyneuropathy (present)
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Pathogenic
(Nov 23, 2022)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002742689.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.110G>C (p.R37P) alteration is located in exon 1 (coding exon 1) of the HINT1 gene. This alteration results from a G to C substitution … (more)
The c.110G>C (p.R37P) alteration is located in exon 1 (coding exon 1) of the HINT1 gene. This alteration results from a G to C substitution at nucleotide position 110, causing the arginine (R) at amino acid position 37 to be replaced by a proline (P). Based on data from the Genome Aggregation Database (gnomAD), the HINT1 c.110G>C alteration was observed in 0.03% (85/281,678) of total alleles studied. The p.R37P alteration, one of three founder mutations and considered to be the most common, has been reported in homozygous and compound heterozygous individuals with autosomal recessive axonal neuropathy with neuromyotonia (Zimo, 2012; Laššuthová, 2015; Jerath, 2015; Shchagina, 2020). This amino acid position is poorly conserved in available vertebrate species. Protein contain p.R37P fails to form functional dimers and exists as monomers, which showed significant loss of secondary structure compared to wild type and showed reduced near UV-absorption indicating incorrect or improper folding (Shah, 2018). This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. (less)
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Pathogenic
(Jul 10, 2021)
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criteria provided, single submitter
Method: clinical testing
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Peripheral neuropathy
Affected status: yes
Allele origin:
germline
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Kariminejad - Najmabadi Pathology & Genetics Center
Accession: SCV001755654.1
First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022 |
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Pathogenic
(Feb 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive axonal neuropathy with neuromyotonia
Affected status: yes
Allele origin:
unknown
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3billion
Accession: SCV003841438.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.030%). Missense changes are a common disease-causing mechanism. … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.030%). Missense changes are a common disease-causing mechanism. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000037312). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 4 similarly affected unrelated individuals (PMID: 22961002, 22961002, 26182879, 27549087). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Muscle spasm (present) , Hyperkinetic movements (present) , Paresthesia (present) , Distal lower limb muscle weakness (present) , Limb ataxia (present) , Hypotrophy of the … (more)
Muscle spasm (present) , Hyperkinetic movements (present) , Paresthesia (present) , Distal lower limb muscle weakness (present) , Limb ataxia (present) , Hypotrophy of the small hand muscles (present) , Distal upper limb muscle weakness (present) , Proximal muscle weakness in lower limbs (present) , Impaired vibratory sensation (present) , Steppage gait (present) , Absent Achilles reflex (present) , Achilles tendon contracture (present) (less)
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Pathogenic
(Jun 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive axonal neuropathy with neuromyotonia
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV004236170.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Pathogenic
(Dec 29, 2023)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive axonal neuropathy with neuromyotonia
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000776537.8
First in ClinVar: Oct 11, 2015 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 37 of the HINT1 protein (p.Arg37Pro). … (more)
This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 37 of the HINT1 protein (p.Arg37Pro). This variant is present in population databases (rs149782619, gnomAD 0.09%). This missense change has been observed in individuals with clinical features of distal hereditary motor neuropathy (PMID: 22961002, 25342199, 26182879, 27549087). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 37312). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jan 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: SCV001245741.24
First in ClinVar: May 12, 2020 Last updated: Aug 04, 2024 |
Comment:
HINT1: PM3:Very Strong, PP1:Strong, PM2, PS3:Supporting, BP4
Number of individuals with the variant: 11
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Pathogenic
(Oct 02, 2019)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive axonal neuropathy with neuromyotonia
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001366390.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PM1,PP2,PP5.
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Pathogenic
(Sep 06, 2022)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive axonal neuropathy with neuromyotonia
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002581875.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PM3_VSTR, PS4_MOD, PS3_SUP, PM2_SUP, PP1
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Number of individuals with the variant: 3
Sex: female
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Pathogenic
(Dec 19, 2022)
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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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GeneDx
Accession: SCV000293545.11
First in ClinVar: Jul 24, 2016 Last updated: Dec 31, 2022 |
Comment:
Published functional studies demonstrate loss of enzyme function in the homozygous state (Zimon et al., 2012); Reported as a founder mutation in the Czech population, … (more)
Published functional studies demonstrate loss of enzyme function in the homozygous state (Zimon et al., 2012); Reported as a founder mutation in the Czech population, accounting for 95% of pathogenic alleles (Lassuthova et al., 2015).; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26182879, 32709422, 22961002, 24918641, 25342199, 26194197, 23043279, 27549087, 29787766, 31787464, 31848916, 34562060, 33726816, 34694653, 33663550) (less)
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Pathogenic
(Oct 01, 2012)
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no assertion criteria provided
Method: literature only
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NEUROMYOTONIA AND AXONAL NEUROPATHY, AUTOSOMAL RECESSIVE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000053527.4
First in ClinVar: Apr 04, 2013 Last updated: Nov 11, 2023 |
Comment on evidence:
In 2 Belgian sibs with autosomal recessive neuromyotonia and axonal neuropathy (NMAN; 137200), Zimon et al. (2012) identified compound heterozygosity for 2 mutations in the … (more)
In 2 Belgian sibs with autosomal recessive neuromyotonia and axonal neuropathy (NMAN; 137200), Zimon et al. (2012) identified compound heterozygosity for 2 mutations in the HINT1 gene: a 110G-C transversion in exon 1, resulting in an arg37-to-pro (R37P) substitution at a nonconserved residue, and a 250T-C transition in exon 3, resulting in a cys84-to-arg (C84R; 601314.0002) substitution at a relatively conserved residue close to the dimer interface important for enzyme activity. The mutations were found by linkage analysis and whole-genome sequencing; neither mutation was found in 270 Belgian controls. C84R was not found in 885 additional controls. In an independent study, linkage analysis and exome sequencing of a consanguineous Austrian family with a similar disorder identified homozygosity for the R37P mutation in 3 affected sibs. Subsequent analysis of this gene in larger cohorts identified 21 additional families who were homozygous for the R37P mutation. The 110G-C change has been reported as a polymorphism (rs149782619), and was heterozygous in 3 of 200 Serbian control individuals. It was also found in 1 of 7,019 European control alleles and in 1 of 3,737 African American control alleles from large exome databases. Haplotype analysis indicated a founder effect for both R37P and C84R. The phenotype was characterized by onset in the first or second decade of a peripheral axonal neuropathy predominantly affecting motor more than sensory nerves. Affected individuals also had action myotonia in the hands and/or neuromyotonic discharges on needle EMG. Heterozygous mutation carriers were unaffected. Complementation studies in yeast showed that the R37P mutant enzyme had no residual activity, whereas the C84R mutant had some residual enzyme activity. Patient lymphoblasts with the R37P and/or C84R mutations showed normal HINT1 mRNA levels, but negligible HINT1 protein expression, suggesting posttranslational degradation. The pathogenic mechanism is thus a loss of function. Zimon et al. (2012) commented that since R37P is predicted to be a benign variant and is found in controls, it could have been discarded during data filtering. However, functional data supported the pathogenicity of the variant in homozygous state. Kontogeorgiou et al. (2021) identified 4 Greek patients with NMAN with R37P mutations, 2 in homozygosity (patients 2 and 3) and 2 in compound heterozygosity (patients 1 and 4) with the C84R mutation (601314.0002). (less)
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Pathogenic
(Apr 25, 2018)
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no assertion criteria provided
Method: clinical testing
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Autosomal recessive axonal neuropathy with neuromyotonia
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics, Cologne University
Accession: SCV000787791.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
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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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HINT1-related neuropathy in Greek patients with Charcot-Marie-Tooth disease. | Kontogeorgiou Z | Journal of the peripheral nervous system : JPNS | 2021 | PMID: 34694653 |
HINT1 gene pathogenic variants: the most common cause of recessive hereditary motor and sensory neuropathies in Russian patients. | Shchagina OA | Molecular biology reports | 2020 | PMID: 31848916 |
Structure and Functional Characterization of Human Histidine Triad Nucleotide-Binding Protein 1 Mutations Associated with Inherited Axonal Neuropathy with Neuromyotonia. | Shah RM | Journal of molecular biology | 2018 | PMID: 29787766 |
Improving diagnosis of inherited peripheral neuropathies through gene panel analysis. | Laššuthová P | Orphanet journal of rare diseases | 2016 | PMID: 27549087 |
A case of neuromyotonia and axonal motor neuropathy: A report of a HINT1 mutation in the United States. | Jerath NU | Muscle & nerve | 2015 | PMID: 26182879 |
Mutations in HINT1 are one of the most frequent causes of hereditary neuropathy among Czech patients and neuromyotonia is rather an underdiagnosed symptom. | Laššuthová P | Neurogenetics | 2015 | PMID: 25342199 |
Loss-of-function mutations in HINT1 cause axonal neuropathy with neuromyotonia. | Zimoń M | Nature genetics | 2012 | PMID: 22961002 |
Text-mined citations for rs149782619 ...
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.