Submissions for variant NM_000143.4(FH):c.208G>A (p.Ala70Thr)

gnomAD frequency: 0.00001  dbSNP: rs587782207

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130874	SCV000185777	likely benign	Hereditary cancer-predisposing syndrome	2022-08-11	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000200494	SCV000251441	uncertain significance	not provided	2023-08-07	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies suggest no damaging effect: demonstrates enzymatic activity and tetramerization similar to wild type (Wilde et al., 2023); This variant is associated with the following publications: (PMID: 28481359, 29684080, 37255402)
Invitae	RCV000200494	SCV000544272	uncertain significance	not provided	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 70 of the FH protein (p.Ala70Thr). This variant is present in population databases (rs587782207, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with FH-related conditions. ClinVar contains an entry for this variant (Variation ID: 142062). 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%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Eurofins Ntd Llc (ga)	RCV000200494	SCV000854830	likely pathogenic	not provided	2018-04-25	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000200494	SCV002774594	uncertain significance	not provided	2021-06-23	criteria provided, single submitter	clinical testing
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153423	SCV003843813	likely pathogenic	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000462728	SCV005057753	uncertain significance	Fumarase deficiency	2024-03-08	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000462728	SCV001455897	uncertain significance	Fumarase deficiency	2020-01-24	no assertion criteria provided	clinical testing