Submissions for variant NM_000143.4(FH):c.668A>C (p.Lys223Thr)

dbSNP: rs1064795294

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000480081	SCV000570966	uncertain significance	not provided	2016-07-11	criteria provided, single submitter	clinical testing	This variant is denoted FH c.668A>C at the cDNA level, p.Lys223Thr (K223T) at the protein level, and results in the change of a Lysine to a Threonine (AAA>ACA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. FH Lys223Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Lysine and Threonine differ in some properties, this is considered a semi-conservative amino acid substitution. FH Lys223Thr occurs at a position that is conserved in mammals and is not located in a known functional domain (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether FH Lys223Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV001025534	SCV001187736	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-22	criteria provided, single submitter	clinical testing	The p.K223T variant (also known as c.668A>C), located in coding exon 5 of the FH gene, results from an A to C substitution at nucleotide position 668. The lysine at codon 223 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000480081	SCV001234657	uncertain significance	not provided	2022-01-26	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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 not expected to disrupt FH protein function. ClinVar contains an entry for this variant (Variation ID: 421681). This variant has not been reported in the literature in individuals affected with FH-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 223 of the FH protein (p.Lys223Thr).
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000480081	SCV005197934	uncertain significance	not provided	2023-06-15	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001069489	SCV001458377	uncertain significance	Fumarase deficiency	2020-09-16	no assertion criteria provided	clinical testing