NM_000143.4(FH):c.698G>T (p.Arg233Leu) AND Hereditary leiomyomatosis and renal cell cancer

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Apr 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:: RCV000017624.46

Allele description [Variation Report for NM_000143.4(FH):c.698G>T (p.Arg233Leu)]

NM_000143.4(FH):c.698G>T (p.Arg233Leu)

Gene:

FH:fumarate hydratase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q43

Genomic location:

Preferred name:

NM_000143.4(FH):c.698G>T (p.Arg233Leu)

Other names:

R190L

HGVS:

NC_000001.11:g.241508643C>A
NG_012338.1:g.16112G>T
NM_000143.4:c.698G>TMANE SELECT
NP_000134.2:p.Arg233Leu
NP_000134.2:p.Arg233Leu
LRG_504t1:c.698G>T
LRG_504:g.16112G>T
LRG_504p1:p.Arg233Leu
NC_000001.10:g.241671943C>A
NM_000143.3:c.698G>T
p.[Arg233Leu]

Protein change:

R233L; ARG190LEU

Links:

OMIM: 136850.0008; dbSNP: rs121913123

NCBI 1000 Genomes Browser:

rs121913123

Molecular consequence:

NM_000143.4:c.698G>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Hereditary leiomyomatosis and renal cell cancer
Synonyms:: Reed syndrome; Multiple cutaneous and uterine leiomyomatosis; Cutaneous leiomyomata with uterine leiomyomata; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007888; MedGen: C1708350; Orphanet: 523; OMIM: 150800; Human Phenotype Ontology: HP:0007437

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Mus musculus choline phosphotransferase 1 (Chpt1), mRNA
Mus musculus choline phosphotransferase 1 (Chpt1), mRNA
gi|38604066|ref|NM_144807.2|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000037900	OMIM	no assertion criteria provided	Pathogenic (Jul 1, 2003)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000537240	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	criteria provided, single submitter (DGD Variant Analysis Guidelines)	Likely pathogenic (Jan 17, 2017)	germline	clinical testing	DGD_Variant_Analysis_Guidelines.docx, Citation Link,
SCV001430110	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	criteria provided, single submitter (Classification criteria August 2017)	Pathogenic (Dec 18, 2017)	germline	clinical testing	Citation Link,
SCV004017822	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Likely pathogenic (Apr 10, 2023)	unknown	clinical testing	PubMed (7) [See all records that cite these PMIDs] 12772087, 16309500, 29423582, 16237213, 33167498, 22677546, 26237645 Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	yes	2	not provided	not provided	1	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America.

Toro JR, Nickerson ML, Wei MH, Warren MB, Glenn GM, Turner ML, Stewart L, Duray P, Tourre O, Sharma N, Choyke P, Stratton P, Merino M, Walther MM, Linehan WM, Schmidt LS, Zbar B.

Am J Hum Genet. 2003 Jul;73(1):95-106. Epub 2003 May 22.

PubMed [citation]

PMID:: 12772087
PMCID:: PMC1180594

Multiple cutaneous and uterine leiomyomata resulting from missense mutations in the fumarate hydratase gene.

Chuang GS, Martinez-Mir A, Engler DE, Gmyrek RF, Zlotogorski A, Christiano AM.

Clin Exp Dermatol. 2006 Jan;31(1):118-21.

PubMed [citation]

PMID:: 16309500

See all PubMed Citations (7)

Details of each submission

From OMIM, SCV000037900.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

Toro et al. (2003) described a family with leiomyomatosis and renal cell cancer (HLRCC; 150800) associated with a 569G-T transversion in exon 4 of the FH gene, resulting in an arg190-to-leu (R190L) mutation. The nucleotide substitution occurred at the same position as that changed in the common R190H mutation (136850.0007).

#	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 Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia, SCV000537240.1

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

From Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München, SCV001430110.1

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

From Myriad Genetics, Inc., SCV004017822.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 12772087, 16309500, 29423582, 16237213, 33167498, 22677546, 26237645]. This variant is expected to disrupt protein structure [Myriad internal data].

#	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

Last Updated: Nov 3, 2024

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