NM_000143.4(FH):c.214A>C (p.Thr72Pro) AND not provided

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Feb 24, 2023
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:: RCV000254803.9

Allele description [Variation Report for NM_000143.4(FH):c.214A>C (p.Thr72Pro)]

NM_000143.4(FH):c.214A>C (p.Thr72Pro)

Gene:

FH:fumarate hydratase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q43

Genomic location:

Preferred name:

NM_000143.4(FH):c.214A>C (p.Thr72Pro)

HGVS:

NC_000001.11:g.241517235T>G
NG_012338.1:g.7520A>C
NM_000143.4:c.214A>CMANE SELECT
NP_000134.2:p.Thr72Pro
NP_000134.2:p.Thr72Pro
LRG_504t1:c.214A>C
LRG_504:g.7520A>C
LRG_504p1:p.Thr72Pro
NC_000001.10:g.241680535T>G
NM_000143.3:c.214A>C

Protein change:

T72P

Links:

dbSNP: rs886039362

NCBI 1000 Genomes Browser:

rs886039362

Molecular consequence:

NM_000143.4:c.214A>C - 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
SCV001227771	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Feb 24, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31831373, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001227771

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Feb 24, 2023)

germline

clinical testing

PubMed (2)
[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	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

Hereditary Leiomyomatosis and Renal Cell Cancer: Clinical, Molecular, and Screening Features in a Cohort of 185 Affected Individuals.

Forde C, Lim DHK, Alwan Y, Burghel G, Butland L, Cleaver R, Dixit A, Evans DG, Hanson H, Lalloo F, Oliveira P, Vialard L, Wallis Y, Maher ER, Woodward ER.

Eur Urol Oncol. 2020 Dec;3(6):764-772. doi: 10.1016/j.euo.2019.11.002. Epub 2019 Dec 9.

PubMed [citation]

PMID:: 31831373

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

Details of each submission

From GeneDx, SCV000321639.7

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

Description

The T72P variant in the FH gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The T72P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant in nearby residue (G69V) has been reported in the Human Gene Mutation Database in association with leiomyomatosis and renal cell cancer (Stenson et al., 2014), supporting the functional importance of this region of the protein. Based on the currently available evidence, it is unclear whether this variant is a pathogenic variant or a rare benign variant. We consider it to be a variant of uncertain significance.

#	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, SCV001227771.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 72 of the FH protein (p.Thr72Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of FH-related conditions (PMID: 31831373; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 265145). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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

Flagged submissions

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000321639	GeneDx	flagged submission Reason: Older and outlier claim with insufficient supporting evidence Notes: None (GeneDx Variant Classification (06012015))	Uncertain significance (Jul 13, 2018)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000321639

GeneDx

flagged submission

Reason: Older and outlier claim with insufficient supporting evidence

Notes: None

(GeneDx Variant Classification (06012015))

Uncertain significance
(Jul 13, 2018)

germline

clinical testing

Citation Link

Last Updated: Sep 29, 2024

ClinVar

Relating variation to medicine