ClinVar Genomic variation as it relates to human health
NM_018344.6(SLC29A3):c.1330G>T (p.Glu444Ter)
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
-
NM_018344.6(SLC29A3):c.1330G>T (p.Glu444Ter)
Variation ID: 564 Accession: VCV000000564.11
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 10q22.1 10: 71362510 (GRCh38) [ NCBI UCSC ] 10: 73122267 (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 Jun 17, 2024 Nov 10, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_018344.6:c.1330G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_060814.4:p.Glu444Ter nonsense NM_001174098.2:c.*559G>T 3 prime UTR NM_001363518.2:c.1096G>T NP_001350447.1:p.Glu366Ter nonsense NR_033413.2:n.1298G>T non-coding transcript variant NR_033414.2:n.1071G>T non-coding transcript variant NC_000010.11:g.71362510G>T NC_000010.10:g.73122267G>T NG_017066.2:g.48252G>T LRG_1318:g.48252G>T LRG_1318t1:c.1330G>T LRG_1318p1:p.Glu444Ter - Protein change
- E444*, E366*
- Other names
- -
- Canonical SPDI
- NC_000010.11:71362509:G:T
-
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.
-
0.00040 (T)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD), exomes 0.00003
Exome Aggregation Consortium (ExAC) 0.00004
1000 Genomes Project 30x 0.00031
1000 Genomes Project 0.00040
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. |
|||
SLC29A3 | - | - |
GRCh38 GRCh37 |
477 | 506 |
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 (3) |
criteria provided, multiple submitters, no conflicts
|
Nov 10, 2023 | RCV000000594.10 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Aug 25, 2017 | RCV000413820.2 |
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. |
|
---|---|---|---|---|---|
Likely pathogenic
(Aug 25, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000490811.2
First in ClinVar: Jan 09, 2017 Last updated: Apr 17, 2019 |
Comment:
The E444X variant in the SLC29A3 gene has been reported previously in the homozygous state in an individual with pigmented hypertrichosis, insulin-dependent diabetes mellitus, and … (more)
The E444X variant in the SLC29A3 gene has been reported previously in the homozygous state in an individual with pigmented hypertrichosis, insulin-dependent diabetes mellitus, and pancreatomegaly; this variant was not observed in over 100 ethnically matched control chromosomes (Cliffe et al., 2009). This variant is predicted to cause loss of normal protein function through protein truncation, as the last 32 amino acids of the protein are lost. While not present in the homozygous state, the E444X variant is observed in 5/16510 (0.03%) alleles from individuals of South Asian background in the ExAC dataset (Lek et al., 2016). We interpret E444X as a likely pathogenic variant. (less)
|
|
Pathogenic
(Nov 10, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
H syndrome
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV001235791.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Glu444*) in the SLC29A3 gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Glu444*) in the SLC29A3 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 32 amino acid(s) of the SLC29A3 protein. This variant is present in population databases (rs267607056, gnomAD 0.03%), including at least one homozygous and/or hemizygous individual. This premature translational stop signal has been observed in individuals with histiocytosis-lymphadenopathy plus syndrome (PMID: 17461801, 19336477, 33947670). ClinVar contains an entry for this variant (Variation ID: 564). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects SLC29A3 function (PMID: 20595384). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts a region of the SLC29A3 protein in which other variant(s) (p.Glu447Lys, p.Thr449Arg) have been observed in individuals with SLC29A3-related conditions (PMID: 19336477, 20595384, 28554179). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
H syndrome
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV005061159.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
Comment:
The observed stop gained variant c.1330G>T(p.Glu444Ter) in SLC29A3 gene has been reported previously in homozygous state in individuals with Histiocytosis-lymphadenopathy syndrome (Mori KS, et al., … (more)
The observed stop gained variant c.1330G>T(p.Glu444Ter) in SLC29A3 gene has been reported previously in homozygous state in individuals with Histiocytosis-lymphadenopathy syndrome (Mori KS, et al., 2021, Cliffe ST, et al., 2009). Experimental evidence showed that this variant shows impairment in protein stability and reduction in nucleoside transport activity (Kang N, et al., 2010).The c.1330G>T variant is reported with 0.003% allele frequency in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic. The nucleotide change c.1330G>T in SLC29A3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Computational evidence (MutationTaster - Disease causing) predicts damaging effect on protein structure and function for this variant. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Abnormality of blood and blood-forming tissues (present)
|
|
Pathogenic
(Sep 03, 2010)
|
no assertion criteria provided
Method: literature only
|
HISTIOCYTOSIS-LYMPHADENOPATHY PLUS SYNDROME
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000020743.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In a 21-year-old East Indian man with pigmented hypertrichosis, lymphadenopathy, and diabetes mellitus (602782), originally reported by Prendiville et al. (2007), Cliffe et al. (2009) … (more)
In a 21-year-old East Indian man with pigmented hypertrichosis, lymphadenopathy, and diabetes mellitus (602782), originally reported by Prendiville et al. (2007), Cliffe et al. (2009) identified homozygosity for a 1330G-T transversion in the SLC29A3 gene, resulting in a glu444-to-ter (E444X) substitution that was predicted to cause premature protein truncation with loss of the final cytoplasmic domain and transmembrane domain 11 of the ENT3 protein. The mutation was not found in more than 100 Lebanese and Pakistani control chromosomes. The patient, who initially presented at age 11 years with proptosis, had an episode of diabetic ketoacidosis at 15 years of age and was diagnosed with type 1 diabetes mellitus, with an elevated anti-GAD65 (138275) titer; at age 16 years he was evaluated for hyperpigmentation and hypertrichosis, which had developed within the previous year. Examination also revealed eyelid infiltrates and episcleritis, hepatosplenomegaly, pancreatomegaly, lymphadenopathy, and dysmorphic features including short stature, long philtrum, an asymmetric chest wall with pectus excavatum, clinodactyly, and flat feet. Kang et al. (2010) performed functional characterization of the E444X mutation in Xenopus oocytes and observed transport activity that was less than half that of wildtype SLC29A3. Studies in NIH 3T3 fibroblasts demonstrated accelerated turnover of the E444X mutant compared to wildtype, suggesting decreased stability. (less)
|
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 |
---|---|---|---|---|
'H-syndrome': a multisystem genetic disorder with cutaneous clues. | Mori KS | BMJ case reports | 2021 | PMID: 33947670 |
Skin-Dominant Phenotype in a Patient with H Syndrome: Identification of a Novel Mutation in the SLC29A3 Gene. | Vural S | Cytogenetic and genome research | 2017 | PMID: 28554179 |
Human equilibrative nucleoside transporter-3 (hENT3) spectrum disorder mutations impair nucleoside transport, protein localization, and stability. | Kang N | The Journal of biological chemistry | 2010 | PMID: 20595384 |
SLC29A3 gene is mutated in pigmented hypertrichosis with insulin-dependent diabetes mellitus syndrome and interacts with the insulin signaling pathway. | Cliffe ST | Human molecular genetics | 2009 | PMID: 19336477 |
Pigmented hypertrichotic dermatosis and insulin dependent diabetes: manifestations of a unique genetic disorder? | Prendiville J | Pediatric dermatology | 2007 | PMID: 17461801 |
Text-mined citations for rs267607056 ...
HelpRecord last updated Jun 23, 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.