NM_000143.4(FH):c.1084G>C (p.Glu362Gln) AND Hereditary cancer-predisposing syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: May 1, 2018
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV002426509.9

Allele description [Variation Report for NM_000143.4(FH):c.1084G>C (p.Glu362Gln)]

NM_000143.4(FH):c.1084G>C (p.Glu362Gln)

Gene:

FH:fumarate hydratase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q43

Genomic location:

Preferred name:

NM_000143.4(FH):c.1084G>C (p.Glu362Gln)

Other names:

E319Q

HGVS:

NC_000001.11:g.241504066C>G
NG_012338.1:g.20689G>C
NM_000143.3:c.1084G>C
NM_000143.4:c.1084G>CMANE SELECT
NP_000134.2:p.Glu362Gln
LRG_504t1:c.1084G>C
LRG_504:g.20689G>C
NC_000001.10:g.241667366C>G

Protein change:

E362Q; GLU319GLN

Links:

OMIM: 136850.0002; dbSNP: rs121913119

NCBI 1000 Genomes Browser:

rs121913119

Molecular consequence:

NM_000143.4:c.1084G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002730510	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (May 1, 2018)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 18313410, 21445611, 8200987 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002730510

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(May 1, 2018)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Differential metabolic consequences of fumarate hydratase and respiratory chain defects.

Raimundo N, Ahtinen J, Fumić K, Barić I, Remes AM, Renkonen R, Lapatto R, Suomalainen A.

Biochim Biophys Acta. 2008 May;1782(5):287-94. doi: 10.1016/j.bbadis.2008.01.008. Epub 2008 Feb 14.

PubMed [citation]

PMID:: 18313410

Structural basis of fumarate hydratase deficiency.

Picaud S, Kavanagh KL, Yue WW, Lee WH, Muller-Knapp S, Gileadi O, Sacchettini J, Oppermann U.

J Inherit Metab Dis. 2011 Jun;34(3):671-6. doi: 10.1007/s10545-011-9294-8. Epub 2011 Mar 29.

PubMed [citation]

PMID:: 21445611
PMCID:: PMC3109261

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV002730510.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The p.E362Q variant (also known as c.1084G>C), located in coding exon 7 of the FH gene, results from a G to C substitution at nucleotide position 1084. The glutamic acid at codon 362 is replaced by glutamine, an amino acid with highly similar properties. Two siblings who were both diagnosed with progressive encephalopathy, dystonia, leukopenia, and neutropenia were found to be homozygous for this variant. The parents of these children were known to be consanguineous and were both found to be heterozygous. Of note, this variant was referred to as E319Q (c.955G>C) in this publication (Bourgeron T et al. J. Clin. Invest. 1994 Jun;93:2514-8). Functional studies performed in fibroblasts of an individual homozygous for the p.E362Q variant indicated an accumulation of fumarate in whole cell lysates showing an overall FH enzymatic deficiency (Raimundo N et al. Biochim. Biophys. Acta. 2008 May;1782:287-94). 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.

#	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: Oct 13, 2024

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