NM_000143.4(FH):c.1431_1433dup (p.Lys477dup) AND not provided
- Somatic classification
of clinical impact: - None
- Review status:
- (0/4) 0 stars out of maximum of 4 starsno assertion criteria provided
- Somatic classification
of oncogenicity: - None
- Review status:
- (0/4) 0 stars out of maximum of 4 starsno assertion criteria provided
- Record status:
- current
- Accession:
- RCV000034483.55
Allele description [Variation Report for NM_000143.4(FH):c.1431_1433dup (p.Lys477dup)]
NM_000143.4(FH):c.1431_1433dup (p.Lys477dup)
- Gene:
- FH:fumarate hydratase [Gene - OMIM - HGNC]
- Variant type:
- Duplication
- Cytogenetic location:
- 1q43
- Genomic location:
- Preferred name:
- NM_000143.4(FH):c.1431_1433dup (p.Lys477dup)
- HGVS:
- NC_000001.10:g.241661227_241661228insTTT
- NC_000001.11:g.241497930_241497932dup
- NG_012338.1:g.26825_26827dup
- NM_000143.4:c.1431_1433dupMANE SELECT
- NP_000134.2:p.Lys477dup
- NP_000134.2:p.Lys477dup
- LRG_504t1:c.1431_1433dup
- LRG_504:g.26825_26827dup
- LRG_504p1:p.Lys477dup
- NC_000001.10:g.241661227_241661228insTTT
- NC_000001.10:g.241661230_241661232dup
- NC_000001.10:g.241661230_241661232dup
- NC_000001.10:g.241661230_241661232dupTTT
- NC_000001.11:g.241497927_241497928insTTT
- NM_000143.2:c.1431_1433dupAAA
- NM_000143.2:c.1433_1434insAAA
- NM_000143.3:c.1431_1433dup
- NM_000143.3:c.1431_1433dupAAA
- NM_000143.4:c.1431_1433dupAAAMANE SELECT
- p.K477dup
- p.Lys477dup
This HGVS expression did not pass validation- Links:
- OMIM: 136850.0012; dbSNP: rs367543046
- NCBI 1000 Genomes Browser:
- rs367543046
- Molecular consequence:
- NM_000143.4:c.1431_1433dup - inframe_insertion - [Sequence Ontology: SO:0001821]
- Observations:
- 12
Condition(s)
- Synonyms:
- none provided
- Identifiers:
- MedGen: C3661900
Assertion and evidence details
Submission Accession | Submitter | Review Status (Assertion method) | Clinical Significance (Last evaluated) | Origin | Method | Citations |
---|---|---|---|---|---|---|
SCV000043258 | Biesecker Lab/Clinical Genomics Section, National Institutes of Health - ClinSeq | no assertion criteria provided | variant of unknown significance (Jul 13, 2012) | germline | research | |
SCV000224779 | Eurofins Ntd Llc (ga) | criteria provided, single submitter (EGL Classification Definitions) | Pathogenic (Jan 20, 2015) | germline | clinical testing | |
SCV000251462 | GeneDx | criteria provided, single submitter (GeneDx Variant Classification Process June 2021) | Pathogenic (Jul 10, 2023) | germline | clinical testing | |
SCV000283665 | Invitae | criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) | Likely pathogenic (Jan 31, 2024) | germline | clinical testing | |
SCV001247136 | CeGaT Center for Human Genetics Tuebingen | criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) | Pathogenic (Dec 1, 2023) | germline | clinical testing | |
SCV001715674 | Mayo Clinic Laboratories, Mayo Clinic | criteria provided, single submitter (ACMG Guidelines, 2015) | Uncertain significance (Jul 16, 2020) | germline | clinical testing | |
SCV001807422 | Genome Diagnostics Laboratory, Amsterdam University Medical Center - VKGL Data-share Consensus | no assertion criteria provided | Pathogenic | germline | clinical testing | |
SCV001958435 | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus
| no assertion criteria provided | Pathogenic | germline | clinical testing | |
SCV002010134 | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | criteria provided, single submitter (ACMG Guidelines, 2015) | Likely pathogenic (Nov 3, 2021) | germline | clinical testing | |
SCV002022987 | Revvity Omics, Revvity | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Mar 29, 2023) | germline | clinical testing | |
SCV002051723 | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | criteria provided, single submitter (ACMG Guidelines, 2015) | Uncertain significance (Jan 28, 2021) | germline | clinical testing | |
SCV002070473 | Genetic Services Laboratory, University of Chicago | criteria provided, single submitter (ACMG Guidelines, 2015) | Likely pathogenic (Mar 19, 2020) | germline | clinical testing | |
SCV002774595 | Quest Diagnostics Nichols Institute San Juan Capistrano | criteria provided, single submitter (Quest Diagnostics criteria) | Uncertain significance (Apr 15, 2023) | unknown | clinical testing | PubMed (41) |
SCV004562079 | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) | Likely pathogenic (Sep 14, 2023) | germline | clinical testing |
Summary from all submissions
Ethnicity | Origin | Affected | Individuals | Families | Chromosomes tested | Number Tested | Family history | Method |
---|---|---|---|---|---|---|---|---|
not provided | germline | no | 5 | not provided | not provided | 572 | not provided | research |
not provided | unknown | unknown | not provided | not provided | not provided | not provided | not provided | clinical testing |
not provided | germline | not provided | not provided | not provided | not provided | not provided | not provided | clinical testing |
not provided | germline | yes | 7 | not provided | not provided | not provided | not provided | clinical testing |
not provided | germline | unknown | 5 | not provided | not provided | not provided | not provided | clinical testing |
Citations
PubMed
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.
Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.
- PMID:
- 28492532
- PMCID:
- PMC5632818
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..
Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.
- PMID:
- 25741868
- PMCID:
- PMC4544753
Details of each submission
From Biesecker Lab/Clinical Genomics Section, National Institutes of Health - ClinSeq, SCV000043258.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | 5 | not provided | not provided | research | PubMed (1) |
Description
The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See PubMed ID:22703879 for details.
Description
Converted during submission to Uncertain significance.
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | no | 572 | not provided | discovery | 5 | not provided | not provided | not provided |
From Eurofins Ntd Llc (ga), SCV000224779.4
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | 4 | not provided | not provided | clinical testing | not provided |
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | unknown | not provided | not provided | not provided | 4 | not provided | not provided | not provided |
From GeneDx, SCV000251462.13
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | not provided |
Description
In-frame duplication of 1 amino acid in a non-repeat region; Recent studies suggest that in the heterozygous state, this variant is not associated with an increased risk to develop HLRCC-related tumors (Zhang et al., 2020; Gupta et al., 2021; Kamihara et al., 2021); This variant has been observed as homozygous in asymptomatic adults tested at GeneDx and in large population cohorts (gnomAD; internal data), suggesting this variant is not associated with FHD when present in the homozygous state; In silico analysis supports a deleterious effect on protein structure/function; Also known as 1302insAAA, Lys434ins, insK477, 435insK, and 435insAAA; This variant is associated with the following publications: (PMID: 28748451, 27051561, 23612258, 2314594, 29319699, 31942411, 31831373, 16151915, 9300800, 9635293, 15987702, 20301679, 27621404, 20549362, 28873162, 29506128, 12761039, 16237213, 28825054, 29641532, 22703879, 18313410, 25985877, 16639410, 21560188, 24441663, 24182348, 16510303, 27541980, 30256826, 29909963, 30426508, 31212687, 28552549, 31444830, 32782288, 31980526, 32581362, 33789101, 33166576, 32413184, 32012241, 33363901, 35626031, 34308104, 35441217, 34289891, 33858029, 31794323, 34994643, 34337822, 35993574, 36556183, 32999401, 29893455, 36773955, 36777509, 33439686, 37255402, 36947458)
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From Invitae, SCV000283665.11
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (13) |
Description
This variant, c.1431_1433dup, results in the insertion of 1 amino acid(s) of the FH protein (p.Lys477dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs367543046, gnomAD 0.5%), including at least one homozygous and/or hemizygous individual. This variant has been observed in combination with other pathogenic FH variants in multiple individuals with autosomal recessive fumarate hydratase deficiency (FHD) (PMID: 9300800, 9635293, 23612258, 16510303, 16151915, 24182348, 27541980, Invitae). However, individuals who are homozygous for this variant do not have clinical features of FHD (gnomAD, Invitae, external communication). It has also been observed as heterozygous in a few individuals with features suggestive of autosomal dominant hereditary leiomyomatosis and renal cell cancer (HLRCC), as well as in unaffected controls (PMID: 23612258, 16639410, 24441663, 25985877, 22703879, Invitae). This variant is also known as c.1433_1434insAAA, c.1431insAAA, c.1433_1434dupAAA, AAAins435, 435insK, InsK477, and 435insAAA. ClinVar contains an entry for this variant (Variation ID: 42095). 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 patient cells carrying this variant and another loss-of-function FH variant have significantly reduced fumarate hydratase enzyme activity (0-20%), compared to wild-type cells (PMID: 9300800, 9635293, 15987702, 16151915, 24182348). No in vitro functional studies measuring the enzymatic activity of this variant alone have been performed. In summary, this is an in-frame duplication that has been observed with several different pathogenic FH variants in multiple affected individuals with FHD. In the homozygous state, this variant does not likely cause FHD, but additional data are needed to prove that conclusively. Although it has been observed as heterozygous in individuals with features of HLRCC, it occurs in the general population too frequently given the rarity of this condition. For these reasons, this variant has been classified as Likely Pathogenic for FHD. However, it is not likely to confer risk for HLRCC.
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From CeGaT Center for Human Genetics Tuebingen, SCV001247136.21
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | 7 | not provided | not provided | clinical testing | not provided |
Description
FH: PS4, PP4:Moderate, PS3:Moderate, PM2:Supporting, PM4:Supporting
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | yes | not provided | not provided | not provided | 7 | not provided | not provided | not provided |
From Mayo Clinic Laboratories, Mayo Clinic, SCV001715674.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | 1 | not provided | not provided | clinical testing | PubMed (1) |
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | unknown | not provided | not provided | not provided | 1 | not provided | not provided | not provided |
From Genome Diagnostics Laboratory, Amsterdam University Medical Center - VKGL Data-share Consensus, SCV001807422.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | not provided |
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001958435.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | not provided |
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden, SCV002010134.3
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | not provided | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From Revvity Omics, Revvity, SCV002022987.3
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center, SCV002051723.2
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
Description
PM3, PM4
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From Genetic Services Laboratory, University of Chicago, SCV002070473.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
Description
DNA sequence analysis of the FH gene demonstrated a three base pair duplication in exon 10, c.1431_1433dup. This pathogenic sequence change results in the duplication of one amino acid residue, p.Lys477dup. The p.Lys477dup sequence change is the most frequent mutant allele observed in patients with autosomal recessive FH-associated fumarate hydratase deficiency (PMID: 20301679). Functional studies have shown that the p.Lys477dup sequence change leads to significantly reduced FH enzyme activity levels (PMID: 15987702).
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV002774595.2
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (41) |
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | unknown | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV004562079.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | not provided |
Description
The FH c.1431_1433dupAAA; p.Lys477dup variant (rs367543046), also known as Lys434ins, 1302insAAA, 1431insAAA, 1433_1434dupAAA, is commonly found in the compound heterozygous state in individuals with fumarase deficiency (Coughlin 1998, Ezgu 2013, Rustin 1997), and is considered the most frequent pathogenic variant associated with fumarase deficiency (Ewbank 2013). It is also reported in the heterozygous state in individuals with cancer predisposition syndrome including hereditary leiomyomatosis and renal cell cancer syndrome (Chen 2014, Ezgu 2013, Martinek 2015, Whitworth 2018). This variant is reported in ClinVar (Variation ID: 42095). It is found in the general population with an overall allele frequency of 0.1% (285/280892 alleles, including 2 homozygotes) in the Genome Aggregation Database. Based on available information, this variant is considered to be likely pathogenic. REFERENCES Chen YB et al. Hereditary leiomyomatosis and renal cell carcinoma syndrome-associated renal cancer: recognition of the syndrome by pathologic features and the utility of detecting aberrant succination by immunohistochemistry. Am J Surg Pathol. 2014 May;38(5):627-37. Coughlin EM et al. Molecular analysis and prenatal diagnosis of human fumarase deficiency. Mol Genet Metab. 1998 Apr;63(4):254-62. Ewbank C et al. Fumarate Hydratase Deficiency. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. SourceGeneReviews (Internet). Seattle (WA): University of Washington, Seattle; 1993-2019. 2006 Jul 5 (updated 2013 Apr 4). Accessed online at: https://www.ncbi.nlm.nih.gov/books/NBK1506/ Ezgu F et al. Mild clinical presentation and prolonged survival of a patient with fumarase deficiency due to the combination of a known and a novel mutation in FH gene. Gene. 2013 Jul 25;524(2):403-6. Martinek P et al. Genetic testing of leiomyoma tissue in women younger than 30 years old might provide an effective screening approach for the hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC). Virchows Arch. 2015 Aug;467(2):185-91. Rustin P et al. Inborn errors of the Krebs cycle: a group of unusual mitochondrial diseases in human. Biochim Biophys Acta. 1997 Aug 22;1361(2):185-97. Whitworth J et al. Comprehensive Cancer-Predisposition Gene Testing in an Adult Multiple Primary Tumor Series Shows a Broad Range of Deleterious Variants and Atypical Tumor Phenotypes. Am J Hum Genet. 2018 Jul 5;103(1):3-18.
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
Last Updated: Jun 2, 2024