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; This variant is associated with the following publications: (PMID: 28772256, 19412178, 27753142, 21393332, 31589614)
ClinVar Genomic variation as it relates to human health
NM_017875.4(SLC25A38):c.324_325del (p.Tyr109fs)
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.
(8)
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/Likely pathogenic
8
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_017875.4(SLC25A38):c.324_325del (p.Tyr109fs)
Variation ID: 1119 Accession: VCV000001119.24
- Type and length
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Microsatellite, 2 bp
- Location
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Cytogenetic: 3p22.1 3: 39391484-39391485 (GRCh38) [ NCBI UCSC ] 3: 39432975-39432976 (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 Mar 20, 2016 Oct 20, 2024 Dec 28, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_017875.4:c.324_325del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_060345.2:p.Tyr109fs frameshift NM_001354798.2:c.324_325del NP_001341727.1:p.Tyr109fs frameshift NM_017875.2:c.324_325delCT NC_000003.12:g.39391484CT[2] NC_000003.11:g.39432975CT[2] NG_016931.1:g.13161CT[2] LRG_1133:g.13161CT[2] LRG_1133t1:c.324_325del LRG_1133p1:p.Tyr109fs - Protein change
- Y109fs
- Other names
- -
- Canonical SPDI
- NC_000003.12:39391483:CTCTCT:CTCT
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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.
- -
- Links
- Comment on variant
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. |
|||
| SLC25A38 | - | - |
GRCh38 GRCh37 |
196 | 227 | |
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
|
Jun 1, 2021 | RCV000001178.8 | |
|
SLC25A38-related disorder
|
Likely pathogenic (1) |
criteria provided, single submitter
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Dec 4, 2018 | RCV000778696.4 |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Dec 28, 2023 | RCV001588793.17 |
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. |
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|---|---|---|---|---|---|
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Pathogenic
(Dec 10, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001822501.3
First in ClinVar: Sep 08, 2021 Last updated: Mar 04, 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; This … (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; This variant is associated with the following publications: (PMID: 28772256, 19412178, 27753142, 21393332, 31589614) (less)
|
|
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Pathogenic
(Dec 28, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003289589.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Tyr109Leufs*43) in the SLC25A38 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Tyr109Leufs*43) in the SLC25A38 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC25A38 are known to be pathogenic (PMID: 19412178, 25985931). This variant is present in population databases (rs535344665, gnomAD 0.04%). This premature translational stop signal has been observed in individuals with congenital sideroblastic anemia (PMID: 19412178, 21393332). ClinVar contains an entry for this variant (Variation ID: 1119). 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 SLC25A38 function (PMID: 19412178). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Pathogenic
(May 27, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005198910.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
|
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Pathogenic
(Dec 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV004702045.8
First in ClinVar: Mar 10, 2024 Last updated: Oct 20, 2024 |
Comment:
SLC25A38: PM3:Very Strong, PVS1, PM2:Supporting
Number of individuals with the variant: 1
|
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Likely pathogenic
(Dec 04, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
SLC25A38-Related Disorders
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000915048.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The SLC25A38 c.324_325delCT (p.Tyr109LeufsTer43) frameshift variant is also reported as c.698_699delCT (p.Leu108fs) in literature. This variant has been reported in at least two studies, in … (more)
The SLC25A38 c.324_325delCT (p.Tyr109LeufsTer43) frameshift variant is also reported as c.698_699delCT (p.Leu108fs) in literature. This variant has been reported in at least two studies, in which it is found in a total of six unrelated individuals with congenital sideroblastic anemia, including in two in a homozygous state and in four in a compound heterozygous state with a second missense or truncating variant (Guernsey et al. 2009; Kannengiesser et al. 2011). This variant is not reported in individuals with pyridoxine-refractory sideroblastic anemia. Control data are unavailable for this variant, which is reported at a frequency of 0.001454 in the European American population of the Exome Sequencing Project. Based on the collective evidence, the p.Tyr109LeufsTer43 variant is classified as likely pathogenic for SLC25A38-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(Jun 01, 2021)
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criteria provided, single submitter
Method: research
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Sideroblastic anemia 2
Affected status: yes
Allele origin:
germline
|
Mark Fleming Laboratory, Boston Children's Hospital
Accession: SCV001736680.1
First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021 |
|
|
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Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Sideroblastic anemia 2
Affected status: yes
Allele origin:
unknown
|
3billion
Accession: SCV004013525.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.017%). The variant is predicted to result in … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.017%). The variant is 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: VCV000001119 / PMID: 19412178). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Exercise intolerance (present) , Abnormality of iron homeostasis (present) , Growth delay (present) , Myopathy (present) , Sideroblastic anemia (present) , Increased circulating lactate concentration … (more)
Exercise intolerance (present) , Abnormality of iron homeostasis (present) , Growth delay (present) , Myopathy (present) , Sideroblastic anemia (present) , Increased circulating lactate concentration (present) , Abnormal echocardiogram (present) (less)
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Pathogenic
(Jun 01, 2009)
|
no assertion criteria provided
Method: literature only
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ANEMIA, SIDEROBLASTIC, 2, PYRIDOXINE-REFRACTORY
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000021328.3
First in ClinVar: Apr 04, 2013 Last updated: Mar 20, 2016 |
Comment on evidence:
In 2 unrelated patients with autosomal recessive sideroblastic anemia-2 (SIDBA2; 205950), Guernsey et al. (2009) identified a homozygous 2-bp deletion (698delCT) in the SLC25A38 gene, … (more)
In 2 unrelated patients with autosomal recessive sideroblastic anemia-2 (SIDBA2; 205950), Guernsey et al. (2009) identified a homozygous 2-bp deletion (698delCT) in the SLC25A38 gene, resulting in a frameshift and premature termination. One patient was of Hispanic descent and the other of European descent. In 4 others patients with sideroblastic anemia, The 698delCT deletion was observed in compound heterozygosity with another putative pathogenic mutation in 4 additional patients with sideroblastic anemia (see, e.g., R187P, 610819.0003). (less)
|
Comment:
Comment:
This sequence change creates a premature translational stop signal (p.Tyr109Leufs*43) in the SLC25A38 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC25A38 are known to be pathogenic (PMID: 19412178, 25985931). This variant is present in population databases (rs535344665, gnomAD 0.04%). This premature translational stop signal has been observed in individuals with congenital sideroblastic anemia (PMID: 19412178, 21393332). ClinVar contains an entry for this variant (Variation ID: 1119). 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 SLC25A38 function (PMID: 19412178). For these reasons, this variant has been classified as Pathogenic.
Comment:
SLC25A38: PM3:Very Strong, PVS1, PM2:Supporting
Comment:
The SLC25A38 c.324_325delCT (p.Tyr109LeufsTer43) frameshift variant is also reported as c.698_699delCT (p.Leu108fs) in literature. This variant has been reported in at least two studies, in which it is found in a total of six unrelated individuals with congenital sideroblastic anemia, including in two in a homozygous state and in four in a compound heterozygous state with a second missense or truncating variant (Guernsey et al. 2009; Kannengiesser et al. 2011). This variant is not reported in individuals with pyridoxine-refractory sideroblastic anemia. Control data are unavailable for this variant, which is reported at a frequency of 0.001454 in the European American population of the Exome Sequencing Project. Based on the collective evidence, the p.Tyr109LeufsTer43 variant is classified as likely pathogenic for SLC25A38-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.017%). The variant is 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: VCV000001119 / PMID: 19412178). 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:
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; This variant is associated with the following publications: (PMID: 28772256, 19412178, 27753142, 21393332, 31589614)
Comment:
This sequence change creates a premature translational stop signal (p.Tyr109Leufs*43) in the SLC25A38 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC25A38 are known to be pathogenic (PMID: 19412178, 25985931). This variant is present in population databases (rs535344665, gnomAD 0.04%). This premature translational stop signal has been observed in individuals with congenital sideroblastic anemia (PMID: 19412178, 21393332). ClinVar contains an entry for this variant (Variation ID: 1119). 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 SLC25A38 function (PMID: 19412178). For these reasons, this variant has been classified as Pathogenic.
Comment:
SLC25A38: PM3:Very Strong, PVS1, PM2:Supporting
Comment:
The SLC25A38 c.324_325delCT (p.Tyr109LeufsTer43) frameshift variant is also reported as c.698_699delCT (p.Leu108fs) in literature. This variant has been reported in at least two studies, in which it is found in a total of six unrelated individuals with congenital sideroblastic anemia, including in two in a homozygous state and in four in a compound heterozygous state with a second missense or truncating variant (Guernsey et al. 2009; Kannengiesser et al. 2011). This variant is not reported in individuals with pyridoxine-refractory sideroblastic anemia. Control data are unavailable for this variant, which is reported at a frequency of 0.001454 in the European American population of the Exome Sequencing Project. Based on the collective evidence, the p.Tyr109LeufsTer43 variant is classified as likely pathogenic for SLC25A38-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.017%). The variant is 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: VCV000001119 / PMID: 19412178). 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 |
|---|---|---|---|---|
| Genotype/phenotype correlations of childhood-onset congenital sideroblastic anaemia in a European cohort. | Fouquet C | British journal of haematology | 2019 | PMID: 31338833 |
| Non syndromic childhood onset congenital sideroblastic anemia: A report of 13 patients identified with an ALAS2 or SLC25A38 mutation. | Le Rouzic MA | Blood cells, molecules & diseases | 2017 | PMID: 28772256 |
| Mutation analysis of Chinese sporadic congenital sideroblastic anemia by targeted capture sequencing. | An W | Journal of hematology & oncology | 2015 | PMID: 25985931 |
| Missense SLC25A38 variations play an important role in autosomal recessive inherited sideroblastic anemia. | Kannengiesser C | Haematologica | 2011 | PMID: 21393332 |
| Mutations in mitochondrial carrier family gene SLC25A38 cause nonsyndromic autosomal recessive congenital sideroblastic anemia. | Guernsey DL | Nature genetics | 2009 | PMID: 19412178 |
Text-mined citations for rs869320719 ...
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.
NCBI staff reviewed the sequence information reported in PubMed 19412178 Supplementary Figure 1B to determine the location of this allele on the current reference sequence.