ClinVar Miner

Submissions for variant NM_000143.4(FH):c.883G>A (p.Ala295Thr)

gnomAD frequency: 0.00018  dbSNP: rs145843819
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166620 SCV000217424 likely benign Hereditary cancer-predisposing syndrome 2020-09-29 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000034485 SCV000815374 uncertain significance not provided 2024-01-16 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 295 of the FH protein (p.Ala295Thr). This variant is present in population databases (rs145843819, gnomAD 0.05%). This missense change has been observed in individual(s) with unspecified cancer (PMID: 28873162). ClinVar contains an entry for this variant (Variation ID: 41583). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FH protein function. 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.
GeneDx RCV000034485 SCV001793187 uncertain significance not provided 2024-03-27 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Observed in at least one individual with unspecified cancer and in an individual with atherosclerosis (PMID: 22703879, 28873162); This variant is associated with the following publications: (PMID: 24728327, 28873162, 22703879)
Sema4, Sema4 RCV000166620 SCV002535578 uncertain significance Hereditary cancer-predisposing syndrome 2021-12-28 criteria provided, single submitter curation
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000034485 SCV002774167 likely benign not provided 2023-04-23 criteria provided, single submitter clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health RCV000034485 SCV000043261 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
ITMI RCV000121091 SCV000085259 not provided not specified 2013-09-19 no assertion provided reference population
Natera, Inc. RCV000687788 SCV001457344 uncertain significance Fumarase deficiency 2020-09-16 no assertion criteria provided clinical testing

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