ClinVar Genomic variation as it relates to human health

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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 FGG protein function. ClinVar contains an entry for this variant (Variation ID: 627235). This missense change has been observed in individual(s) with clinical features consistent with a fibrinogen abnormality (PMID: 24556703, 30418131, 31064749). This variant is present in population databases (rs138511699, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 47 of the FGG protein (p.Thr47Ile). 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.

Variant summary: FGG c.140C>T (p.Thr47Ile) results in a non-conservative amino acid change located in the Fibrinogen, alpha/beta/gamma chain, coiled coil domain (IPR012290) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00056 in 244160 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in FGG causing Congenital Dysfibrinogenemia, allowing no conclusion about variant significance. c.140C>T has been reported in the literature as a non-informative genotype (second allele not specified) in an otherwise asymptomatic female with hypofibrinogenemia (example, Riedelova-Reicheltova_2014); as a non-informative genotype (second allele not specified) in an individual with unexplained bleeding in whom a partial contribution to the patient phenotype was reported (example, Downes_2019) and as a compound heterozygous genotype in a female with hypodysfibrinogenaemia and clinical features of pregnancy-related thrombosis (example, Chinni_2019). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30418131, 31064749, 24556703, 23560673, 37647632). ClinVar contains an entry for this variant (Variation ID: 627235). Based on the evidence outlined above, the variant was classified as uncertain significance.

FGG: BS1:Supporting

The FGG c.140C>T variant is predicted to result in the amino acid substitution p.Thr47Ile. This variant (aka p.Thr21Ile) has been reported in the heterozygous state in two individuals with decreased fibrinogen (Riedelová-Reicheltová et al. 2014. PubMed ID: 24556703). In addition, this variant was reported in the compound heterozygous state in a female with hypo-dysfibrinogenemia and pregnancy-related venous thrombosis; this variant was also found in her asymptomatic mother (Chinni et al. 2018. PubMed ID: 30418131). This variant has also been reported in an individual with unexplained bleeding (Downes et al. 2019. PubMed ID: 31064749. Suppl3_SNV+INDEL). This variant is reported in 0.076% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.