NM_000143.4(FH):c.1023T>G (p.Asp341Glu) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jul 26, 2021
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:: RCV000493972.10

Allele description [Variation Report for NM_000143.4(FH):c.1023T>G (p.Asp341Glu)]

NM_000143.4(FH):c.1023T>G (p.Asp341Glu)

Gene:

FH:fumarate hydratase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q43

Genomic location:

Preferred name:

NM_000143.4(FH):c.1023T>G (p.Asp341Glu)

HGVS:

NC_000001.11:g.241504127A>C
NG_012338.1:g.20628T>G
NM_000143.4:c.1023T>GMANE SELECT
NP_000134.2:p.Asp341Glu
NP_000134.2:p.Asp341Glu
LRG_504t1:c.1023T>G
LRG_504:g.20628T>G
LRG_504p1:p.Asp341Glu
NC_000001.10:g.241667427A>C
NM_000143.3:c.1023T>G

Protein change:

D341E

Links:

dbSNP: rs863223973

NCBI 1000 Genomes Browser:

rs863223973

Molecular consequence:

NM_000143.4:c.1023T>G - 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
SCV000581631	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Jul 26, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000581631

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Jul 26, 2021)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

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

Structural, biochemical and biophysical characterization of recombinant human fumarate hydratase.

Ajalla Aleixo MA, Rangel VL, Rustiguel JK, de Pádua RAP, Nonato MC.

FEBS J. 2019 May;286(10):1925-1940. doi: 10.1111/febs.14782. Epub 2019 Mar 7.

PubMed [citation]

PMID:: 30761759

Details of each submission

From Ambry Genetics, SCV000581631.6

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

Description

The p.D341E pathogenic mutation (also known as c.1023T>G), located in coding exon 7 of the FH gene, results from a T to G substitution at nucleotide position 1023. The aspartic acid at codon 341 is replaced by glutamic acid, an amino acid with highly similar properties. This alteration has been observed in at least two unrelated individuals with a personal and/or family history that is consistent with HLRCC-related disease (Ambry internal data). Based on internal structural analysis, this variant decreases structural stability (Ajalla Aleixo MA et al. FEBS J, 2019 05;286:1925-1940). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is not well conserved in available vertebrate species. 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.

#	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 26, 2024

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