ClinVar Genomic variation as it relates to human health
NM_015346.4(ZFYVE26):c.5260G>A (p.Ala1754Thr)
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_015346.4(ZFYVE26):c.5260G>A (p.Ala1754Thr)
Variation ID: 219623 Accession: VCV000219623.37
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q24.1 14: 67775076 (GRCh38) [ NCBI UCSC ] 14: 68241793 (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 Feb 2, 2016 May 12, 2024 Mar 26, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_015346.4:c.5260G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_056161.2:p.Ala1754Thr missense NC_000014.9:g.67775076C>T NC_000014.8:g.68241793C>T NG_011836.1:g.46514G>A - Protein change
- A1754T
- Other names
- -
- Canonical SPDI
- NC_000014.9:67775075:C:T
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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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0.00020 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
Exome Aggregation Consortium (ExAC) 0.00027
The Genome Aggregation Database (gnomAD), exomes 0.00037
Trans-Omics for Precision Medicine (TOPMed) 0.00042
The Genome Aggregation Database (gnomAD) 0.00045
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00085
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 | ||
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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
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. |
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ZFYVE26 | - | - |
GRCh38 GRCh37 |
2730 | 2952 |
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. |
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Uncertain significance (1) |
criteria provided, single submitter
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Sep 19, 2022 | RCV000203761.3 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Mar 26, 2024 | RCV000517780.3 | |
Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
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May 25, 2020 | RCV000763939.9 | |
Uncertain significance (5) |
criteria provided, multiple submitters, no conflicts
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Jan 1, 2021 | RCV001311360.21 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 1, 2019 | RCV001847926.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 11, 2021 | RCV002515515.3 |
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
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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Uncertain significance
(Feb 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Athena Diagnostics
Accession: SCV000616322.1
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
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Uncertain significance
(Sep 19, 2022)
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criteria provided, single submitter
Method: clinical testing
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Spastic paraplegia
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000259604.3
First in ClinVar: Feb 02, 2016 Last updated: Mar 26, 2023 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1754 of the ZFYVE26 protein (p.Ala1754Thr). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1754 of the ZFYVE26 protein (p.Ala1754Thr). This variant is present in population databases (rs146968463, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with ZFYVE26-related conditions. ClinVar contains an entry for this variant (Variation ID: 219623). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hereditary spastic paraplegia 15
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000894885.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Uncertain significance
(Jan 12, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hereditary spastic paraplegia 15
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001278096.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
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Uncertain significance
(Sep 06, 2019)
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criteria provided, single submitter
Method: clinical testing
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Spastic paraplegia 15, autosomal recessive
Affected status: unknown
Allele origin:
germline
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Knight Diagnostic Laboratories, Oregon Health and Sciences University
Accession: SCV001448832.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Number of individuals with the variant: 1
Clinical Features:
Migraine (present) , Peripheral neuropathy (present) , Skin rash (present) , Arthralgia (present) , IgA deficiency (present) , IgG deficiency (present) , IgM deficiency (present) … (more)
Migraine (present) , Peripheral neuropathy (present) , Skin rash (present) , Arthralgia (present) , IgA deficiency (present) , IgG deficiency (present) , IgM deficiency (present) , Fever (present) , Goiter (present) , Heat intolerance (present) , Immunodeficiency (present) , Abnormality of B cell number (present) , Decreased antibody level in blood (present) (less)
Sex: male
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Uncertain significance
(Nov 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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Hereditary spastic paraplegia
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, The Hospital for Sick Children
Accession: SCV002106077.1
First in ClinVar: Mar 19, 2022 Last updated: Mar 19, 2022 |
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Uncertain significance
(May 25, 2020)
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criteria provided, single submitter
Method: clinical testing
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Hereditary spastic paraplegia 15
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002766600.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
A heterozygous missense variant was identified, NM_015346.3(ZFYVE26):c.5260G>A in exon 27 of 42 of the ZFYVE26 gene. This substitution is predicted to create a moderate amino … (more)
A heterozygous missense variant was identified, NM_015346.3(ZFYVE26):c.5260G>A in exon 27 of 42 of the ZFYVE26 gene. This substitution is predicted to create a moderate amino acid change from an alanine to a threonine at position 1754 of the protein; NP_056161.2(ZFYVE26):p.(Ala1754Thr). The alanine at this position has low conservation (100 vertebrates, UCSC), and is located within the retinal superfamily domain (NCBI). In silico software predicts this variant to be tolerated (PolyPhen2, PROVEAN, MutationAssessor, FATHMM). The variant is present in the gnomAD population database at a global population frequency of 0.04% (104 heterozygotes, 0 homozygotes) with a European sub-population frequency of 0.07%. This variant has not previously been reported in clinical cases. Based on information available at the time of curation, this variant has been classified as a VUS with LOW CLINICAL RELEVANCE. (less)
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Uncertain significance
(Dec 13, 2019)
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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: SCV001988298.2
First in ClinVar: Nov 05, 2021 Last updated: Mar 04, 2023 |
Comment:
In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as … (more)
In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge (less)
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Uncertain significance
(Jun 11, 2021)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV003550760.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
The c.5260G>A (p.A1754T) alteration is located in exon 27 (coding exon 26) of the ZFYVE26 gene. This alteration results from a G to A substitution … (more)
The c.5260G>A (p.A1754T) alteration is located in exon 27 (coding exon 26) of the ZFYVE26 gene. This alteration results from a G to A substitution at nucleotide position 5260, causing the alanine (A) at amino acid position 1754 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Jan 01, 2021)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001501512.18
First in ClinVar: Mar 14, 2021 Last updated: May 12, 2024 |
Number of individuals with the variant: 1
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Uncertain significance
(Mar 26, 2024)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV005039078.1
First in ClinVar: May 07, 2024 Last updated: May 07, 2024 |
Comment:
Variant summary: ZFYVE26 c.5260G>A (p.Ala1754Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign … (more)
Variant summary: ZFYVE26 c.5260G>A (p.Ala1754Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00037 in 248244 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ZFYVE26 causing Hereditary Spastic Paraplegia 15 (0.00037 vs ND), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.5260G>A in individuals affected with Hereditary Spastic Paraplegia 15 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 219623). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Study: VKGL Data-share Consensus
Accession: SCV001799932.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001931780.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001976010.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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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
HelpThere are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar. |
Text-mined citations for rs146968463 ...
HelpRecord last updated May 12, 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.