ClinVar Genomic variation as it relates to human health
NM_000143.4(FH):c.1157A>G (p.Gln386Arg)
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_000143.4(FH):c.1157A>G (p.Gln386Arg)
Variation ID: 405939 Accession: VCV000405939.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q43 1: 241502522 (GRCh38) [ NCBI UCSC ] 1: 241665822 (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 1, 2018 May 1, 2024 Jan 17, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000143.4:c.1157A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000134.2:p.Gln386Arg missense NC_000001.11:g.241502522T>C NC_000001.10:g.241665822T>C NG_012338.1:g.22233A>G LRG_504:g.22233A>G LRG_504t1:c.1157A>G LRG_504p1:p.Gln386Arg - Protein change
- Q386R
- Other names
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- Canonical SPDI
- NC_000001.11:241502521:T:C
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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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FH | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1976 | 2062 |
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 (1) |
criteria provided, single submitter
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Mar 6, 2023 | RCV000562894.11 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jul 13, 2022 | RCV001551727.13 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 17, 2024 | RCV004017625.2 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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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
(Apr 15, 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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GeneDx
Accession: SCV001772295.1
First in ClinVar: Aug 07, 2021 Last updated: Aug 07, 2021 |
Comment:
Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.Gln343Arg; This variant is associated with the following publications: (PMID: 31524643, 21398687, 27097334, 28300276, 27161211, 29655270, 25292446) (less)
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Likely pathogenic
(Mar 06, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000664717.5
First in ClinVar: Jan 01, 2018 Last updated: Apr 15, 2023 |
Comment:
The p.Q386R variant (also known as c.1157A>G), located in coding exon 8 of the FH gene, results from an A to G substitution at nucleotide … (more)
The p.Q386R variant (also known as c.1157A>G), located in coding exon 8 of the FH gene, results from an A to G substitution at nucleotide position 1157. The glutamine at codon 386 is replaced by arginine, an amino acid with highly similar properties. This alteration has been detected in individuals with HLRCC and fumarate hydratase-deficient renal cell carcinoma (Gardie B et al. J Med Genet, 2011 Apr;48:226-34; Llamas-Velasco M et al. J Cutan Pathol, 2014 Nov;41:859-65; Muller M et al. Clin Genet, 2017 Dec;92:606-615; Lau HD et al. Am J Surg Pathol, 2020 01;44:98-110). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
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Pathogenic
(Jul 13, 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: SCV000544290.9
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
Comment:
ClinVar contains an entry for this variant (Variation ID: 405939). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that … (more)
ClinVar contains an entry for this variant (Variation ID: 405939). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects FH function (PMID: 21398687). 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 FH protein function. This variant is also known as c.1028A>G (p.Gln343Arg). This missense change has been observed in individual(s) with a personal and family history of hereditary leiomyomatosis and renal cell cancer (HLRCC) and hereditary leiomyomatosis and renal cell cancer (HLRCC) (PMID: 21398687, 25292446). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 386 of the FH protein (p.Gln386Arg). (less)
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Likely Pathogenic
(Nov 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary leiomyomatosis and renal cell cancer
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004848814.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Gln386Arg (historically referred to as Gln343Arg) variant in FH has been reported in at least 3 individuals with hereditary leiomyomatosis and renal cell cancer … (more)
The p.Gln386Arg (historically referred to as Gln343Arg) variant in FH has been reported in at least 3 individuals with hereditary leiomyomatosis and renal cell cancer (HLRCC) and segregated with disease in >5 relatives (Gardie 2011 PubMed: 21398687; Muller 2017 PubMed: 28300276). It was also observed in ClinVar (Variation ID 405939) but absent in gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Studies on patient blood samples or derived cell lines demonstrate reduced FH activity (Gardie 2011 PubMed: 21398687; Muller 2017,PubMed: 28300276). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HLRCC. ACMG/AMP Criteria applied: PS4_Moderate, PP1_Moderate, PM2_Supporting, PP3, PP4. (less)
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Pathogenic
(Jan 17, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hereditary leiomyomatosis and renal cell cancer
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV004933811.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
Comment:
This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 33789101, 31524643, 25292446, 21398687, 28300276]. … (more)
This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 33789101, 31524643, 25292446, 21398687, 28300276]. Functional studies indicate this variant impacts protein function [PMID: 21398687, 25292446, 27097334]. This variant is expected to disrupt protein structure [Myriad internal data]. (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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Trans-ethnic variation in germline variants of patients with renal cell carcinoma. | Abou Alaiwi S | Cell reports | 2021 | PMID: 33789101 |
A Clinicopathologic and Molecular Analysis of Fumarate Hydratase-deficient Renal Cell Carcinoma in 32 Patients. | Lau HD | The American journal of surgical pathology | 2020 | PMID: 31524643 |
Reassessing the clinical spectrum associated with hereditary leiomyomatosis and renal cell carcinoma syndrome in French FH mutation carriers. | Muller M | Clinical genetics | 2017 | PMID: 28300276 |
Loss of Fumarate Hydratase and Aberrant Protein Succination Detected With S-(2-Succino)-Cysteine Staining to Identify Patients With Multiple Cutaneous and Uterine Leiomyomatosis and Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome. | Llamas-Velasco M | The American Journal of dermatopathology | 2016 | PMID: 27097334 |
Fumarate hydratase immunohistochemical staining may help to identify patients with multiple cutaneous and uterine leiomyomatosis (MCUL) and hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome. | Llamas-Velasco M | Journal of cutaneous pathology | 2014 | PMID: 25292446 |
Novel FH mutations in families with hereditary leiomyomatosis and renal cell cancer (HLRCC) and patients with isolated type 2 papillary renal cell carcinoma. | Gardie B | Journal of medical genetics | 2011 | PMID: 21398687 |
Text-mined citations for rs750447792 ...
HelpRecord last updated Jul 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.