ClinVar Genomic variation as it relates to human health
NM_014053.4(FLVCR1):c.1158T>G (p.Ile386Met)
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_014053.4(FLVCR1):c.1158T>G (p.Ile386Met)
Variation ID: 450159 Accession: VCV000450159.21
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q32.3 1: 212885358 (GRCh38) [ NCBI UCSC ] 1: 213058700 (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 Dec 19, 2017 Apr 15, 2024 Nov 1, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_014053.4:c.1158T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_054772.1:p.Ile386Met missense NC_000001.11:g.212885358T>G NC_000001.10:g.213058700T>G NG_028131.1:g.32104T>G - Protein change
- I386M
- Other names
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- Canonical SPDI
- NC_000001.11:212885357: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
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00025
The Genome Aggregation Database (gnomAD), exomes 0.00028
The Genome Aggregation Database (gnomAD) 0.00032
Exome Aggregation Consortium (ExAC) 0.00035
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00054
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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FLVCR1 | - | - |
GRCh38 GRCh37 |
461 | 545 |
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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Uncertain significance (6) |
criteria provided, multiple submitters, no conflicts
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Nov 1, 2023 | RCV000522010.14 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Mar 8, 2022 | RCV001099906.6 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 26, 2021 | RCV002527604.1 |
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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Uncertain significance
(Jul 06, 2017)
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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: SCV000618705.1
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
Comment:
The I386M variant in the FLVCR1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. Although … (more)
The I386M variant in the FLVCR1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. Although not present in the homozygous state, the I386M variant is observed in 18/16512 (0.11%) alleles from individuals of South Asian background in the ExAC dataset (Lek et al., 2016). The I386M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Isoleucine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret I386M as a variant of uncertain significance. (less)
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Uncertain significance
(Jan 13, 2018)
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criteria provided, single submitter
Method: clinical testing
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Posterior column ataxia-retinitis pigmentosa syndrome
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001256398.1
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
(Mar 08, 2022)
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criteria provided, single submitter
Method: clinical testing
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Posterior column ataxia-retinitis pigmentosa syndrome
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002786735.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Oct 24, 2022)
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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: SCV001224358.4
First in ClinVar: Apr 15, 2020 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 386 of the FLVCR1 protein (p.Ile386Met). … (more)
This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 386 of the FLVCR1 protein (p.Ile386Met). This variant is present in population databases (rs149834738, gnomAD 0.1%). This missense change has been observed in individual(s) with apparently non-syndromic retinitis pigmentosa (PMID: 30656474). ClinVar contains an entry for this variant (Variation ID: 450159). 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 not expected to disrupt FLVCR1 protein function. 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
(Mar 26, 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: SCV003589837.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
The c.1158T>G (p.I386M) alteration is located in exon 5 (coding exon 5) of the FLVCR1 gene. This alteration results from a T to G substitution … (more)
The c.1158T>G (p.I386M) alteration is located in exon 5 (coding exon 5) of the FLVCR1 gene. This alteration results from a T to G substitution at nucleotide position 1158, causing the isoleucine (I) at amino acid position 386 to be replaced by a methionine (M). The p.I386M alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
Number of individuals with the variant: 1
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Uncertain significance
(Jul 07, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics Inc
Accession: SCV001143947.3
First in ClinVar: Jan 19, 2020 Last updated: Jan 26, 2024 |
Comment:
Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is … (more)
Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene (http://gnomad.broadinstitute.org). Computational tools disagree on the variant's effect on normal protein function. (less)
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Uncertain significance
(Nov 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004184010.3
First in ClinVar: Dec 24, 2023 Last updated: Apr 15, 2024 |
Comment:
FLVCR1: PP4
Number of individuals with the variant: 1
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Uncertain significance
(-)
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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, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001922741.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Uncertain significance
(-)
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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: SCV001972578.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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not provided
(-)
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no classification provided
Method: phenotyping only
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Posterior column ataxia-retinitis pigmentosa syndrome
Affected status: unknown
Allele origin:
unknown
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GenomeConnect - Invitae Patient Insights Network
Accession: SCV001749854.1
First in ClinVar: Jul 18, 2021 Last updated: Jul 18, 2021 |
Comment:
Variant interpreted as Uncertain significance and reported on 05-22-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided … (more)
Variant interpreted as Uncertain significance and reported on 05-22-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less)
Clinical Features:
Abnormality of vision (present) , Myopia (present) , Abnormal retinal morphology (present) , Vertigo (present) , Tinnitus (present) , Abnormality of the cardiovascular system (present) … (more)
Abnormality of vision (present) , Myopia (present) , Abnormal retinal morphology (present) , Vertigo (present) , Tinnitus (present) , Abnormality of the cardiovascular system (present) , Stroke disorder (present) , Asthma (present) , Respiratory insufficiency (present) , Bleeding with minor or no trauma (present) , Bruising susceptibility (present) , Abnormal erythrocyte morphology (present) , Autoimmunity (present) , Recurrent infections (present) , Abnormal intestine morphology (present) , Abnormality of the pancreas (present) , Abnormal large intestine morphology (present) , Abnormal muscle physiology (present) , Abnormality of the musculature of the limbs (present) , Precocious puberty (present) , Abnormality of the bladder (present) , Abnormality of the female genitalia (present) , Abnormality of reproductive system physiology (present) , Abnormal renal physiology (present) , Abnormality of urine homeostasis (present) , Seizure (present) , Abnormality of movement (present) , Anxiety (present) , Depression (present) , Compulsive behaviors (present) , Abnormal delivery (present) (less)
Indication for testing: Diagnostic
Age: 50-59 years
Sex: female
Testing laboratory: Invitae
Date variant was reported to submitter: 2020-05-22
Testing laboratory interpretation: Uncertain significance
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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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Comprehensive genomic diagnosis of inherited retinal and optical nerve disorders reveals hidden syndromes and personalized therapeutic options. | Diñeiro M | Acta ophthalmologica | 2020 | PMID: 32483926 |
Phenotypic spectrum of autosomal recessive retinitis pigmentosa without posterior column ataxia caused by mutations in the FLVCR1 gene. | Kuehlewein L | Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie | 2019 | PMID: 30656474 |
Text-mined citations for rs149834738 ...
HelpRecord last updated Apr 15, 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.