ClinVar Genomic variation as it relates to human health
NM_021095.4(SLC5A6):c.422_423del (p.Val141fs)
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_021095.4(SLC5A6):c.422_423del (p.Val141fs)
Variation ID: 975021 Accession: VCV000975021.11
- Type and length
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Microsatellite, 2 bp
- Location
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Cytogenetic: 2p23.3 2: 27206913-27206914 (GRCh38) [ NCBI UCSC ] 2: 27429781-27429782 (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 Aug 10, 2020 Feb 4, 2024 Jun 22, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_021095.4:c.422_423del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_066918.2:p.Val141fs frameshift NM_021095.2:c.422_423del NM_021095.2:c.422_423delTG NR_028323.2:n.876TG[1] non-coding transcript variant NC_000002.12:g.27206913CA[1] NC_000002.11:g.27429781CA[1] - Protein change
- V141fs
- Other names
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- Canonical SPDI
- NC_000002.12:27206912:CACA:CA
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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.
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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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SLC5A6 | - | - |
GRCh38 GRCh37 |
73 | 102 |
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
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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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Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Dec 24, 2022 | RCV001251428.6 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 22, 2023 | RCV002069329.7 |
Submissions - Germline
Classification
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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
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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
(Oct 15, 2020)
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criteria provided, single submitter
Method: clinical testing
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Neurodegeneration, infantile-onset, biotin-responsive
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002556869.2
First in ClinVar: Aug 08, 2022 Last updated: Dec 17, 2022 |
Comment:
The SLC5A6 c.422_423delTG frameshift variant is classified as LIKELY PATHOGENIC (PS4_supporting, PVS1) This SLC5A6 c.422_423delTG variant is located in exon 4 and is predicted to … (more)
The SLC5A6 c.422_423delTG frameshift variant is classified as LIKELY PATHOGENIC (PS4_supporting, PVS1) This SLC5A6 c.422_423delTG variant is located in exon 4 and is predicted to cause a shift in the reading frame at codon 141. This variant has been reported in a sibling pair with an infantile-onset, progressive neurodegerative disorder, in a compound heterozygous state with a missense variant (PMID: 31754459) (PS4_moderate). In that study, reduced expression of the frameshift allele is suggestive of nonsense-mediated decay. This variant is in dbSNP (rs749980819) and has been reported in population databases (gnomAD allele frequency = 0.010%, 29 het and 0 hom in 282846 sequenced alleles). This variant has been reported in the HGMD disease database as damaging for the neurodegenerative disorder listed above (CD1919409) (less)
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Likely pathogenic
(Dec 24, 2022)
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criteria provided, single submitter
Method: clinical testing
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Neurodegeneration, infantile-onset, biotin-responsive
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002819799.1
First in ClinVar: Jan 15, 2023 Last updated: Jan 15, 2023 |
Comment:
Variant summary: SLC5A6 c.422_423delTG (p.Val141Alafs*34) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: SLC5A6 c.422_423delTG (p.Val141Alafs*34) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 9.5e-05 in 251472 control chromosomes. This frequency does not allow conclusions about variant significance. c.422_423delTG has been reported in the literature in individuals affected with Neurodegeneration, Infantile-Onset, Biotin-Responsive (example, Byrne_2019, Holling_2022 citing Schwantje_2019). These data indicate that the variant may be associated with disease. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported although expression of the Val141Alafs*34 truncated allele was decreased compared to wild-type (Byrne_2019). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Likely pathogenic
(Jun 22, 2023)
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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: SCV002496287.3
First in ClinVar: Apr 08, 2022 Last updated: Aug 18, 2023 |
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Functional … (more)
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Functional studies suggest a damaging effect: impaired biotin uptake (Byrne et al., 2019); This variant is associated with the following publications: (PMID: 31754459, 31392107, 35013551, Moldenhauer_2023_Abstract) (less)
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Pathogenic
(Nov 10, 2021)
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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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Revvity Omics, Revvity
Accession: SCV002020717.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jun 02, 2022)
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no assertion criteria provided
Method: literature only
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SODIUM-DEPENDENT MULTIVITAMIN TRANSPORTER DEFICIENCY
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV001427036.2
First in ClinVar: Aug 10, 2020 Last updated: Jun 10, 2022 |
Comment on evidence:
In 2 sibs with sodium-dependent multivitamin transporter deficiency (SMVTD; 618973), Byrne et al. (2019) identified compound heterozygous mutations in the SLC5A6 gene: a 2-bp deletion … (more)
In 2 sibs with sodium-dependent multivitamin transporter deficiency (SMVTD; 618973), Byrne et al. (2019) identified compound heterozygous mutations in the SLC5A6 gene: a 2-bp deletion (c.422_423delTG, chr2.27,429,780GCA-G, GRCh37), resulting in a frameshift and premature termination (Val141AlafsTer34), and a c.1199G-C transversion, resulting in an arg400-to-thr (R400T; 604024.0004) substitution at a conserved residue in an intracellular loop. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Both mutations were observed at a low frequency in the heterozygous state in the gnomAD database. Expression of the frameshift transcript was decreased compared to controls, suggesting nonsense-mediated mRNA decay, whereas R400T was expressed normally. In vitro studies of patient fibroblasts showed decreased biotin uptake compared to the parents, although the change was not statistically significant compared to controls. However, HeLa cells transfected with the mutations showed impaired biotin uptake compared to controls, consistent with a loss of function. In a 3-year-old girl with SMVTD, Schwantje et al. (2019) identified compound heterozygous 2-bp deletions in the SLC5A6 gene: c.422_423del and c.1865_1866del (604024.0005) in the last exon, predicted to result in a frameshift (Gln622fs) and extension of the protein by 37 amino acids. The mutations, which were found by trio-based whole-exome sequencing, were each inherited from an unaffected parent. Functional studies of the variants and studies of patient cells were not performed. She presented in infancy with severe feeding difficulties, poor growth, gastroesophageal reflux disease, and persistent vomiting with traces of blood. She later developed metabolic acidosis and acute neurologic and cardiorespiratory decompensation associated with gastroenteritis. Laboratory studies showed hypoglycemia and hyperammonemia, and biochemical features suggesting biotin deficiency; biotin supplementation was initiated. After the genetic diagnosis was established, the biotin dose was increased and pantothenic acid was added, resulting in resolution of the diarrhea and improved growth, although gross motor delay was still noted. Schwantje et al. (2019) emphasized that infection may unmask this metabolic disorder. (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 expand the SLC5A6-related phenotypic spectrum. | Holling T | European journal of human genetics : EJHG | 2022 | PMID: 35013551 |
Identification and targeted management of a neurodegenerative disorder caused by biallelic mutations in SLC5A6. | Byrne AB | NPJ genomic medicine | 2019 | PMID: 31754459 |
Genetic defect of the sodium-dependent multivitamin transporter: A treatable disease, mimicking biotinidase deficiency. | Schwantje M | JIMD reports | 2019 | PMID: 31392107 |
Text-mined citations for rs749980819 ...
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.