This sequence change creates a premature translational stop signal (p.Arg148*) in the NDRG1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NDRG1 are known to be pathogenic (PMID: 12872253, 23996628). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with autosomal recessive Charcot–Marie–Tooth (PMID: 10831399, 17470135, 21892769, 23996628, 25108819, 25231362). It is commonly reported in individuals of Roma ancestry (PMID: 25108819, 25231362). ClinVar contains an entry for this variant (Variation ID: 5120). For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_006096.4(NDRG1):c.442C>T (p.Arg148Ter)
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.
(11)
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
11
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_006096.4(NDRG1):c.442C>T (p.Arg148Ter)
Variation ID: 5120 Accession: VCV000005120.47
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 8q24.22 8: 133258374 (GRCh38) [ NCBI UCSC ] 8: 134270617 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Apr 4, 2013 Oct 20, 2024 Sep 5, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_006096.4:c.442C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006087.2:p.Arg148Ter nonsense NM_001135242.2:c.442C>T NP_001128714.1:p.Arg148Ter nonsense NM_001258432.2:c.244C>T NP_001245361.1:p.Arg82Ter nonsense NM_001258433.2:c.199C>T NP_001245362.1:p.Arg67Ter nonsense NM_001374844.1:c.442C>T NP_001361773.1:p.Arg148Ter nonsense NM_001374845.1:c.442C>T NP_001361774.1:p.Arg148Ter nonsense NM_001374846.1:c.442C>T NP_001361775.1:p.Arg148Ter nonsense NM_001374847.1:c.244C>T NP_001361776.1:p.Arg82Ter nonsense NC_000008.11:g.133258374G>A NC_000008.10:g.134270617G>A NG_007943.1:g.43882C>T LRG_258:g.43882C>T LRG_258t1:c.442C>T LRG_258p1:p.Arg148Ter - Protein change
- R148*, R67*, R82*
- Other names
- -
- Canonical SPDI
- NC_000008.11:133258373:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
- 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. |
|||
| NDRG1 | - | - |
GRCh38 GRCh37 |
713 | 873 | |
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 (6) |
criteria provided, multiple submitters, no conflicts
|
Sep 5, 2023 | RCV000005427.14 | |
| Pathogenic (2) |
criteria provided, single submitter
|
Aug 10, 2023 | RCV000469692.11 | |
| Pathogenic (3) |
criteria provided, single submitter
|
May 1, 2022 | RCV001092150.26 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Sep 05, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Charcot-Marie-Tooth disease type 4D
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV004031452.1
First in ClinVar: Sep 09, 2023 Last updated: Sep 09, 2023 |
Clinical Features:
Pes cavus (present) , Clubfoot (present) , Areflexia of lower limbs (present) , Demyelinating peripheral neuropathy (present) , Progressive pes cavus (present) , Hand muscle … (more)
Pes cavus (present) , Clubfoot (present) , Areflexia of lower limbs (present) , Demyelinating peripheral neuropathy (present) , Progressive pes cavus (present) , Hand muscle weakness (present) (less)
|
|
|
Pathogenic
(Jul 25, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Charcot-Marie-Tooth disease type 4D
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002018236.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Aug 10, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Charcot-Marie-Tooth disease type 4
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000551845.7
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg148*) in the NDRG1 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg148*) in the NDRG1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NDRG1 are known to be pathogenic (PMID: 12872253, 23996628). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with autosomal recessive Charcot–Marie–Tooth (PMID: 10831399, 17470135, 21892769, 23996628, 25108819, 25231362). It is commonly reported in individuals of Roma ancestry (PMID: 25108819, 25231362). ClinVar contains an entry for this variant (Variation ID: 5120). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Jan 01, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Charcot-Marie-Tooth disease type 4D
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001440965.1
First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020 |
|
|
|
Pathogenic
(Feb 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Charcot-Marie-Tooth disease type 4D
Affected status: yes
Allele origin:
unknown
|
3billion
Accession: SCV003841450.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. This variant was predicted to result in a loss or disruption of normal protein function … (more)
The variant is not observed in the gnomAD v2.1.1 dataset. This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000005120 / PMID: 10831399). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Dysarthria (present) , Distal amyotrophy (present) , Distal muscle weakness (present) , Proximal muscle weakness (present) , Impaired vibration sensation in the lower limbs (present) … (more)
Dysarthria (present) , Distal amyotrophy (present) , Distal muscle weakness (present) , Proximal muscle weakness (present) , Impaired vibration sensation in the lower limbs (present) , Somatic sensory dysfunction (present) , Reduced tendon reflexes (present) , Pes cavus (present) , Split hand (present) (less)
|
|
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Pathogenic
(May 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001248527.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 6
|
|
|
Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Charcot-Marie-Tooth disease type 4
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001462052.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001924604.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001959454.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
|
Pathogenic
(Apr 01, 2007)
|
no assertion criteria provided
Method: literature only
|
CHARCOT-MARIE-TOOTH DISEASE, DEMYELINATING, TYPE 4D
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000025609.2
First in ClinVar: Apr 04, 2013 Last updated: Sep 16, 2024 |
Comment on evidence:
In an analysis of the NDRG1 gene in 60 individuals affected with hereditary motor and sensory neuropathy-Lom, or Charcot-Marie-Tooth disease type 4D (CMT4D; 601455), Kalaydjieva … (more)
In an analysis of the NDRG1 gene in 60 individuals affected with hereditary motor and sensory neuropathy-Lom, or Charcot-Marie-Tooth disease type 4D (CMT4D; 601455), Kalaydjieva et al. (2000) identified a C-to-T transition in exon 7 at nucleotide 564 that resulted in an arg148-to-ter (R148X) mutation. The mutation was found in homozygous state in all 60 patients. The disorder was diagnosed in diverse Gypsy populations across Europe. Morar et al. (2004) used the R148X mutation and 4 other private mutations among the Roma (Gypsies) to infer some of the missing parameters relevant to the comprehensive characterization of the population history of the Gypsies. Sharing of mutations and high carrier rates supported a strong founder effect. Claramunt et al. (2007) found that 4 of 20 Spanish Gypsy families with autosomal recessive demyelinating neuropathy had CMT4D due to homozygosity for the R148X mutation. (less)
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Charcot-Marie-Tooth disease type 4D
Affected status: not provided
Allele origin:
unknown
|
GeneReviews
Accession: SCV000054532.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
|
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| click to load more click to collapse | |||||
Comment:
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000005120 / PMID: 10831399). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
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:
This sequence change creates a premature translational stop signal (p.Arg148*) in the NDRG1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NDRG1 are known to be pathogenic (PMID: 12872253, 23996628). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with autosomal recessive Charcot–Marie–Tooth (PMID: 10831399, 17470135, 21892769, 23996628, 25108819, 25231362). It is commonly reported in individuals of Roma ancestry (PMID: 25108819, 25231362). ClinVar contains an entry for this variant (Variation ID: 5120). For these reasons, this variant has been classified as Pathogenic.
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000005120 / PMID: 10831399). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Charcot-Marie-Tooth Neuropathy Type 4 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY. | Adam MP | - | 2016 | PMID: 20301641 |
| Unraveling the genetic landscape of autosomal recessive Charcot-Marie-Tooth neuropathies using a homozygosity mapping approach. | Zimoń M | Neurogenetics | 2015 | PMID: 25231362 |
| Clinical, electrophysiological and pathological findings in a patient with Charcot-Marie-Tooth disease 4D caused by the NDRG1 Lom mutation. | Luigetti M | Journal of the neurological sciences | 2014 | PMID: 25108819 |
| Founder mutations in NDRG1 and HK1 genes are common causes of inherited neuropathies among Roma/Gypsies in Slovakia. | Gabrikova D | Journal of applied genetics | 2013 | PMID: 23996628 |
| SNP array-based whole genome homozygosity mapping as the first step to a molecular diagnosis in patients with Charcot-Marie-Tooth disease. | Fischer C | Journal of neurology | 2012 | PMID: 21892769 |
| The p.R1109X mutation in SH3TC2 gene is predominant in Spanish Gypsies with Charcot-Marie-Tooth disease type 4. | Claramunt R | Clinical genetics | 2007 | PMID: 17470135 |
| Mutation history of the roma/gypsies. | Morar B | American journal of human genetics | 2004 | PMID: 15322984 |
| Mutation screening of the N-myc downstream-regulated gene 1 (NDRG1) in patients with Charcot-Marie-Tooth Disease. | Hunter M | Human mutation | 2003 | PMID: 12872253 |
| N-myc downstream-regulated gene 1 is mutated in hereditary motor and sensory neuropathy-Lom. | Kalaydjieva L | American journal of human genetics | 2000 | PMID: 10831399 |
Text-mined citations for rs119483085 ...
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.