ClinVar Miner

Submissions for variant NM_000143.4(FH):c.305C>T (p.Ala102Val)

gnomAD frequency: 0.00003  dbSNP: rs61753295
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165037 SCV000215735 uncertain significance Hereditary cancer-predisposing syndrome 2024-02-12 criteria provided, single submitter clinical testing The p.A102V variant (also known as c.305C>T), located in coding exon 3 of the FH gene, results from a C to T substitution at nucleotide position 305. The alanine at codon 102 is replaced by valine, an amino acid with similar properties. This alteration was identified in a cohort of 1040 patients with advanced cancer; however, specific clinical information on this individual was not provided (Mandelker D et al. JAMA, 2017 09;318:825-835). This alteration was also identified in 1/1358 non-cancer control individuals and in 0/57 cases, in a study looking at cancer predisposition mutations in patients with cutaneous melanoma and a history of at least two additional non-cutaneous melanoma primary cancers (Pritchard AL et al. PLoS One, 2018 Apr;13:e0194098).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 available evidence, the clinical significance of this alteration remains unclear.
Illumina Laboratory Services, Illumina RCV000388495 SCV000356721 likely benign Hereditary leiomyomatosis and renal cell cancer 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina RCV000388495 SCV000356722 uncertain significance Hereditary leiomyomatosis and renal cell cancer 2016-06-14 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000349307 SCV000356723 uncertain significance Fumarase deficiency 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp RCV001582651 SCV000544265 uncertain significance not provided 2024-01-06 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 102 of the FH protein (p.Ala102Val). This variant is present in population databases (rs61753295, gnomAD 0.006%). 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: 185591). 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.
GeneDx RCV001582651 SCV001813413 uncertain significance not provided 2021-04-21 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal or family history including renal cell carcinoma and an unspecified advanced cancer (Dalgliesh 2010, Mandelker 2017); This variant is associated with the following publications: (PMID: 20054297, 28873162, 18366737)
Natera, Inc. RCV000349307 SCV002085881 uncertain significance Fumarase deficiency 2020-08-27 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.