ClinVar Genomic variation as it relates to human health
NM_001080442.3(SLC38A8):c.848A>C (p.Asp283Ala)
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.
Pathogenic(1); Likely pathogenic(2); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001080442.3(SLC38A8):c.848A>C (p.Asp283Ala)
Variation ID: 372508 Accession: VCV000372508.10
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16q23.3 16: 84017245 (GRCh38) [ NCBI UCSC ] 16: 84050850 (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 Jan 9, 2017 Feb 14, 2024 Jan 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001080442.3:c.848A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001073911.1:p.Asp283Ala missense NC_000016.10:g.84017245T>G NC_000016.9:g.84050850T>G NG_034136.1:g.29913A>C - Protein change
- D283A
- Other names
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- Canonical SPDI
- NC_000016.10:84017244:T: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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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00024
Trans-Omics for Precision Medicine (TOPMed) 0.00027
The Genome Aggregation Database (gnomAD), exomes 0.00028
Exome Aggregation Consortium (ExAC) 0.00031
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00038
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
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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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SLC38A8 | - | - |
GRCh38 GRCh37 |
616 | 694 |
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/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 31, 2024 | RCV000413331.6 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Jun 2, 2023 | RCV000991179.5 |
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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Likely pathogenic
(Jan 26, 2016)
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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: SCV000490813.1
First in ClinVar: Jan 09, 2017 Last updated: Jan 09, 2017 |
Comment:
The D283A variant in the SLC38A8 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The … (more)
The D283A variant in the SLC38A8 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The D283A variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The D283A variant is a non-conservative amino acid substitution that occurs at a position which is highly conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. A single amino acid deletion of an adjacent residue (A282del) has been reported in the compound heterozygous state in two sisters affected with foveal hypoplasia and optic nerve decussation defects, supporting the functional importance of this region of the protein (Poulter et al., 2013). The D283A variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. (less)
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Uncertain significance
(Apr 08, 2020)
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criteria provided, single submitter
Method: clinical testing
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Foveal hypoplasia - optic nerve decussation defect - anterior segment dysgenesis syndrome
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
paternal
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Undiagnosed Diseases Network, NIH
Study: Undiagnosed Diseases Network (NIH), UDN
Accession: SCV001432155.1 First in ClinVar: Sep 14, 2020 Last updated: Sep 14, 2020 |
Comment:
This variant was observed in a patient with foveal hypoplasia and a second likely pathogenic variant.
Number of individuals with the variant: 1
Clinical Features:
Tubulointerstitial fibrosis (present) , Tubular atrophy (present) , Reduced ejection fraction (present) , Proteinuria (present) , Podocyte foot process effacement (present) , Peripheral neuropathy (present) … (more)
Tubulointerstitial fibrosis (present) , Tubular atrophy (present) , Reduced ejection fraction (present) , Proteinuria (present) , Podocyte foot process effacement (present) , Peripheral neuropathy (present) , Palpitations (present) , Nystagmus (present) , Muscular hypotonia (present) , Muscle weakness (present) , Muscle cramps (present) , Mesangial abnormality (present) , Infantile muscular hypotonia (present) , Glomerulomegaly (present) , Elevated serum creatine phosphokinase (present) , Elevated plasma acylcarnitine levels (present) , Deep venous thrombosis (present) , Cellulitis (present) (less)
Age: 30-39 years
Sex: male
Ethnicity/Population group: Causasians
Tissue: blood
Testing laboratory: HudsonAlpha Clinical Services Lab, LLC,HudsonAlpha Clinical Services Lab, LLC
Date variant was reported to submitter: 2018-08-09
Testing laboratory interpretation: Uncertain significance
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Likely pathogenic
(Jun 02, 2023)
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criteria provided, single submitter
Method: clinical testing
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Foveal hypoplasia - optic nerve decussation defect - anterior segment dysgenesis syndrome
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV004238665.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002300948.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 283 of the SLC38A8 protein … (more)
This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 283 of the SLC38A8 protein (p.Asp283Ala). This variant is present in population databases (rs139373929, gnomAD 0.6%). This missense change has been observed in individuals with autosomal recessive foveal hypoplasia (PMID: 28546991, 29345414, 33498813; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 372508). 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 SLC38A8 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. (less)
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Uncertain significance
(Jan 06, 2020)
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no assertion criteria provided
Method: curation
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Foveal hypoplasia 2, with or without optic nerve misrouting and/or anterior segment dysgenesis
Affected status: unknown
Allele origin:
germline
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Reproductive Health Research and Development, BGI Genomics
Accession: SCV001142464.1
First in ClinVar: Jan 12, 2020 Last updated: Jan 12, 2020 |
Comment:
NM_001080442.1:c.848A>C in the SLC38A8 gene has an allele frequency of 0.006 in Ashkenazi Jewish subpopulation in the gnomAD database. Pathogenic computational verdict because pathogenic predictions … (more)
NM_001080442.1:c.848A>C in the SLC38A8 gene has an allele frequency of 0.006 in Ashkenazi Jewish subpopulation in the gnomAD database. Pathogenic computational verdict because pathogenic predictions from DANN, EIGEN, FATHMM-MKL, M-CAP, MutationAssessor, MutationTaster, PrimateAI, REVEL and SIFT. We interpret it as variant of uncertain significance (VUS). ACMG/AMP criteria applied: PP3. (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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Novel Biallelic Variants and Phenotypic Features in Patients with SLC38A8-Related Foveal Hypoplasia. | Schiff ER | International journal of molecular sciences | 2021 | PMID: 33498813 |
Molecular characterization of a series of 990 index patients with albinism. | Lasseaux E | Pigment cell & melanoma research | 2018 | PMID: 29345414 |
Structural modeling of a novel SLC38A8 mutation that causes foveal hypoplasia. | Toral MA | Molecular genetics & genomic medicine | 2017 | PMID: 28546991 |
Text-mined citations for rs139373929 ...
HelpRecord last updated Mar 17, 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.