NM_000143.4(FH):c.1097G>A (p.Ser366Asn) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Feb 20, 2024
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:: RCV000200592.20

Allele description [Variation Report for NM_000143.4(FH):c.1097G>A (p.Ser366Asn)]

NM_000143.4(FH):c.1097G>A (p.Ser366Asn)

Gene:

FH:fumarate hydratase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q43

Genomic location:

Preferred name:

NM_000143.4(FH):c.1097G>A (p.Ser366Asn)

Other names:

p.S366N:AGT>AAT

HGVS:

NC_000001.11:g.241504053C>T
NG_012338.1:g.20702G>A
NM_000143.4:c.1097G>AMANE SELECT
NP_000134.2:p.Ser366Asn
NP_000134.2:p.Ser366Asn
LRG_504t1:c.1097G>A
LRG_504:g.20702G>A
LRG_504p1:p.Ser366Asn
NC_000001.10:g.241667353C>T
NM_000143.3:c.1097G>A

Protein change:

S366N

Links:

dbSNP: rs863224004

NCBI 1000 Genomes Browser:

rs863224004

Molecular consequence:

NM_000143.4:c.1097G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000251478	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Feb 20, 2024)	germline	clinical testing	Citation Link,
SCV000283661	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 31, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 12761039, 12772087, 16237213, 28492532
SCV004218860	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Jul 26, 2023)	unknown	clinical testing	PubMed (8) [See all records that cite these PMIDs] 12761039, 12772087, 16237213, 21630274, 31299266, 21445611, 31831373, 26467025

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000251478

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Feb 20, 2024)

germline

clinical testing

Citation Link,

SCV000283661

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 31, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV004218860

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Pathogenic
(Jul 26, 2023)

unknown

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Genetic and functional analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer, and fumarate hydratase deficiency.

Alam NA, Rowan AJ, Wortham NC, Pollard PJ, Mitchell M, Tyrer JP, Barclay E, Calonje E, Manek S, Adams SJ, Bowers PW, Burrows NP, Charles-Holmes R, Cook LJ, Daly BM, Ford GP, Fuller LC, Hadfield-Jones SE, Hardwick N, Highet AS, Keefe M, MacDonald-Hull SP, et al.

Hum Mol Genet. 2003 Jun 1;12(11):1241-52.

PubMed [citation]

PMID:: 12761039

See all PubMed Citations (9)

Details of each submission

From GeneDx, SCV000251478.17

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

Description

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 FH c.968G>A, p.Ser323Asn; This variant is associated with the following publications: (PMID: 15937070, 12761039, 31299266, 18366737, 21630274, 12772087, 16597677, 16029320, 16237213, 30761759, 22561013, 35022142, 31831373, 21445611)

#	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, SCV000283661.11

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 366 of the FH protein (p.Ser366Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with multiple cutaneous and uterine leiomyomatosis (MCUL) or hereditary leiomyomatosis and renal cell cancer (HLRCC) (PMID: 12761039, 12772087, 16237213; Invitae). This variant is also known as G968A or S323N. ClinVar contains an entry for this variant (Variation ID: 214419). 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 with a positive predictive value of 95%. 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 Quest Diagnostics Nichols Institute San Juan Capistrano, SCV004218860.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

The FH c.1097G>A (p.Ser366Asn) variant has been reported in the published literature in individuals with phenotypes associated with hereditary leiomyomatosis and renal cell cancer (HLRCC)(PMID: 12772087 (2003), 16237213 (2005), 21630274 (2011), 31299266 (2019)). Immunohistochemical analysis of tumors from patients with this variant showed loss of heterozygosity and were positive for (2-succinyl) cysteine (2SC) (termed protein succination) due to deficient fumarase (PMID: 21630274 (2011)). Additionally, this variant is predicted to alter the active site of the FH protein (PMID: 21445611 (2011), 12761039 (2003)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic.

#	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: Sep 29, 2024

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