NM_000143.4(FH):c.697C>T (p.Arg233Cys) AND not provided

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Oct 10, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000153237.37

Allele description [Variation Report for NM_000143.4(FH):c.697C>T (p.Arg233Cys)]

NM_000143.4(FH):c.697C>T (p.Arg233Cys)

Gene:

FH:fumarate hydratase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q43

Genomic location:

Preferred name:

NM_000143.4(FH):c.697C>T (p.Arg233Cys)

HGVS:

NC_000001.11:g.241508644G>A
NG_012338.1:g.16111C>T
NM_000143.4:c.697C>TMANE SELECT
NP_000134.2:p.Arg233Cys
NP_000134.2:p.Arg233Cys
LRG_504t1:c.697C>T
LRG_504:g.16111C>T
LRG_504p1:p.Arg233Cys
NC_000001.10:g.241671944G>A
NM_000143.3:c.697C>T
p.R233C

Links:

dbSNP: rs587781682

NCBI 1000 Genomes Browser:

rs587781682

Molecular consequence:

NM_000143.4:c.697C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000230852	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions)	Pathogenic (Feb 19, 2014)	germline	clinical testing	Citation Link,
SCV000251418	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Feb 1, 2022)	germline	clinical testing	Citation Link,
SCV000632484	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 10, 2023)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 15761418, 2314594, 9300800, 21398687, 21445611, 11865300, 12772087, 15937070, 17960613, 20618355, 22127509, 28492532
SCV002544394	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (May 1, 2022)	germline	clinical testing	Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	4	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Germline fumarate hydratase mutations and evidence for a founder mutation underlying multiple cutaneous and uterine leiomyomata.

Chuang GS, Martinez-Mir A, Geyer A, Engler DE, Glaser B, Cserhalmi-Friedman PB, Gordon D, Horev L, Lukash B, Herman E, Cid MP, Brenner S, Landau M, Sprecher E, Garcia Muret MP, Christiano AM, Zlotogorski A.

J Am Acad Dermatol. 2005 Mar;52(3 Pt 1):410-6.

PubMed [citation]

PMID:: 15761418

Fumarase deficiency is an autosomal recessive encephalopathy affecting both the mitochondrial and the cytosolic enzymes.

Gellera C, Uziel G, Rimoldi M, Zeviani M, Laverda A, Carrara F, DiDonato S.

Neurology. 1990 Mar;40(3 Pt 1):495-9.

PubMed [citation]

PMID:: 2314594

See all PubMed Citations (12)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000230852.5

#	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, SCV000251418.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Observed in trans or phase unknown with FH Lys477dup (also known as Lys434ins) in children with fumarase deficiency (Gellera 1990, Chakravorty 2020); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.Arg190Cys; This variant is associated with the following publications: (PMID: 16639410, 28300276, 21445611, 11865300, 16597677, 9300800, 18366737, 15761418, 20618355, 12612654, 21404119, 2314594, 15937070, 28152038, 32999401, 21398687)

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000632484.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

Description

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 233 of the FH protein (p.Arg233Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hereditary leiomyomatosis and renal cell cancer and fumarate hydratase deficiency (PMID: 2314594, 9300800, 15761418, 15937070, 21398687; Invitae). This variant is also known as c.568C>T, p.Arg190Cys. ClinVar contains an entry for this variant (Variation ID: 141355). 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. Experimental studies have shown that this missense change affects FH function (PMID: 2314594, 9300800, 21398687, 21445611). This variant disrupts the p.Arg233 amino acid residue in FH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11865300, 12772087, 15937070, 17960613, 20618355, 22127509). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

#	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, SCV002544394.14

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

Description

FH: PM1:Strong, PM2, PM5, PP3, PS3: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		1	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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