ClinVar Genomic variation as it relates to human health
NM_018344.6(SLC29A3):c.1309G>A (p.Gly437Arg)
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_018344.6(SLC29A3):c.1309G>A (p.Gly437Arg)
Variation ID: 565 Accession: VCV000000565.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q22.1 10: 71362489 (GRCh38) [ NCBI UCSC ] 10: 73122246 (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 Jul 25, 2015 Sep 16, 2024 May 28, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_018344.6:c.1309G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_060814.4:p.Gly437Arg missense NM_001174098.2:c.*538G>A 3 prime UTR NM_001363518.2:c.1075G>A NP_001350447.1:p.Gly359Arg missense NR_033413.2:n.1277G>A non-coding transcript variant NR_033414.2:n.1050G>A non-coding transcript variant NC_000010.11:g.71362489G>A NC_000010.10:g.73122246G>A NG_017066.2:g.48231G>A LRG_1318:g.48231G>A LRG_1318t1:c.1309G>A LRG_1318p1:p.Gly437Arg Q9BZD2:p.Gly437Arg - Protein change
- G437R, G359R
- Other names
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- Canonical SPDI
- NC_000010.11:71362488:G:A
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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.
The Genome Aggregation Database (gnomAD), exomes 0.00005
Trans-Omics for Precision Medicine (TOPMed) 0.00005
The Genome Aggregation Database (gnomAD) 0.00006
Exome Aggregation Consortium (ExAC) 0.00007
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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SLC29A3 | - | - |
GRCh38 GRCh37 |
479 | 508 |
Conditions - Germline
Condition
Help
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
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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 (5) |
criteria provided, multiple submitters, no conflicts
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Mar 29, 2024 | RCV000000595.14 | |
Pathogenic (1) |
criteria provided, single submitter
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May 28, 2024 | RCV000414664.3 |
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
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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
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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 28, 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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GeneDx
Accession: SCV000491053.3
First in ClinVar: Jan 09, 2017 Last updated: Sep 16, 2024 |
Comment:
Functional study in Xenopus oocytes suggested that G437R retains some transport activity but leads to decreased stability of the mutant protein (PMID: 20595384); however, more … (more)
Functional study in Xenopus oocytes suggested that G437R retains some transport activity but leads to decreased stability of the mutant protein (PMID: 20595384); however, more studies are needed to confirm the actual effect of this sequence change; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24547910, 18940313, 29041934, 20619369, 20140240, 32341814, 33029882, 31589614, 35732371, 20595384) (less)
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Pathogenic
(Oct 05, 2021)
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criteria provided, single submitter
Method: clinical testing
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H syndrome
Affected status: yes
Allele origin:
unknown
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Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV001976844.1
First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
Comment:
PS1, PM2, PP3, PP5
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Pathogenic
(Mar 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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H syndrome
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002318457.1
First in ClinVar: Apr 02, 2022 Last updated: Apr 02, 2022 |
Comment:
Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000000565). The … (more)
Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000000565). The variant has been reported to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated families (PMID: 20595384). Functional assays showed that the variant had moderate level of impact on gene/protein function (PMID: 20595384). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.69>=0.6). The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000516). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Clinodactyly (present) , Global developmental delay (present) , Growth delay (present) , Hyperpigmented nevi (present) , Hypochromic microcytic anemia (present) , Myopia (present) , Reticulocytopenia … (more)
Clinodactyly (present) , Global developmental delay (present) , Growth delay (present) , Hyperpigmented nevi (present) , Hypochromic microcytic anemia (present) , Myopia (present) , Reticulocytopenia (present) , Sensorineural hearing loss disorder (present) , Short stature (present) , Delayed speech and language development (present) , Edema (present) (less)
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Pathogenic
(Jan 03, 2024)
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criteria provided, single submitter
Method: clinical testing
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H syndrome
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000825940.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 437 of the SLC29A3 protein (p.Gly437Arg). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 437 of the SLC29A3 protein (p.Gly437Arg). This variant is present in population databases (rs121912584, gnomAD 0.007%). This missense change has been observed in individual(s) with H syndrome and pigmented hypertrichosis with insulin dependent diabetes (PHID) (PMID: 18940313, 20619369, 29041934). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 565). 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 SLC29A3 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SLC29A3 function (PMID: 20595384). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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H syndrome
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004807689.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
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Pathogenic
(Sep 03, 2010)
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no assertion criteria provided
Method: literature only
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HISTIOCYTOSIS-LYMPHADENOPATHY PLUS SYNDROME
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000020744.2
First in ClinVar: Apr 04, 2013 Last updated: Jul 25, 2015 |
Comment on evidence:
In 10 patients who were diagnosed with H syndrome, involving cutaneous hyperpigmentation with hypertrichosis, hepatosplenomegaly, heart anomalies, hearing loss, and hypogonadism (602782), Molho-Pessach et al. … (more)
In 10 patients who were diagnosed with H syndrome, involving cutaneous hyperpigmentation with hypertrichosis, hepatosplenomegaly, heart anomalies, hearing loss, and hypogonadism (602782), Molho-Pessach et al. (2008) identified homozygosity for a 1309G-A transition in exon 6 of the SLC29A3 gene, resulting in a gly437-to-arg (G437R) substitution. Five of the families were known to be consanguineous. Another H syndrome patient was found to be compound heterozygous for the G427S (612373.0001) and G437R mutations in the SLC29A3 gene; that patient came from a consanguineous Arab family residing in a village between the villages of 2 other H syndrome families, who were each homozygous for 1 of the mutations, respectively. Analysis of 212 geographically and ethnically matched chromosomes revealed 2 heterozygous individuals, indicating a 1% frequency of the disease allele in this Arab population near Jerusalem. The mutation was not found in 60 chromosomes from Jewish individuals or in 76 control chromosomes from individuals of European or Bulgarian origin. In an 18-year-old Lebanese Australian man, born of first-cousin parents, who had hyperpigmentation, hypertrichosis, hepatosplenomegaly, lymphadenopathy, and elevated inflammatory markers, originally reported by Prendiville et al. (2007), Cliffe et al. (2009) identified homozygosity for the G437R mutation in the SLC29A3 gene. The mutation was not found in more than 100 Lebanese and Pakistani control chromosomes. The patient also had apparent lipoatrophy of the lower extremities, and trivial aortic incompetence due to a bicommissural aortic valve. In 2 Palestinian brothers diagnosed with Faisalabad histiocytosis, originally reported by Rossbach et al. (2006), Morgan et al. (2010) identified homozygosity for the G437R substitution in the SLC29A3 gene. Both brothers had intrauterine fractures, short stature, sensorineural deafness, and lymphadenopathy. In 3 Turkish brothers with sinus histiocytosis and massive lymphadenopathy (familial Rosai-Dorfman disease), previously studied by Kismet et al. (2005), Morgan et al. (2010) identified compound heterozygosity for G437R and a 2-bp deletion (c.307delTT) in exon 3 of the SLC29A3 gene, predicted to result in an immediate phe103-to-ter (F103X; 612373.0009) substitution. Additional features in this family included short stature, sensorineural deafness, and hepatomegaly. The mutations segregated with disease in both families and were not found in 192 Turkish or 84 Arab control chromosomes, respectively. Kang et al. (2010) performed functional characterization of the G437R mutation in Xenopus oocytes and observed transport activity that was approximately half that of wildtype SLC29A3. Studies in NIH 3T3 fibroblasts demonstrated accelerated turnover of the G437R mutant compared to wildtype, suggesting decreased stability. (less)
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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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H syndrome: 5 new cases from the United States with novel features and responses to therapy. | Bloom JL | Pediatric rheumatology online journal | 2017 | PMID: 29041934 |
Expanding the clinical spectrum of SLC29A3 gene defects. | Spiegel R | European journal of medical genetics | 2010 | PMID: 20619369 |
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 |
Mutations in SLC29A3, encoding an equilibrative nucleoside transporter ENT3, cause a familial histiocytosis syndrome (Faisalabad histiocytosis) and familial Rosai-Dorfman disease. | Morgan NV | PLoS genetics | 2010 | PMID: 20140240 |
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 |
The H syndrome is caused by mutations in the nucleoside transporter hENT3. | Molho-Pessach V | American journal of human genetics | 2008 | PMID: 18940313 |
Pigmented hypertrichotic dermatosis and insulin dependent diabetes: manifestations of a unique genetic disorder? | Prendiville J | Pediatric dermatology | 2007 | PMID: 17461801 |
Faisalabad histiocytosis mimics Rosai-Dorfman disease: brothers with lymphadenopathy, intrauterine fractures, short stature, and sensorineural deafness. | Rossbach HC | Pediatric blood & cancer | 2006 | PMID: 16155931 |
Sinus histiocytosis with massive lymphadenopathy in three brothers. | Kismet E | Pediatrics international : official journal of the Japan Pediatric Society | 2005 | PMID: 16118898 |
Text-mined citations for rs121912584 ...
HelpRecord last updated Sep 29, 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.