Submissions for variant NM_021870.3(FGG):c.124G>A (p.Gly42Ser)

gnomAD frequency: 0.00034  dbSNP: rs202132393

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001145946	SCV001306655	uncertain significance	Congenital afibrinogenemia	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.
CeGaT Center for Human Genetics Tuebingen	RCV001171744	SCV001334582	likely benign	not provided	2020-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001171744	SCV001986327	uncertain significance	not provided	2019-11-11	criteria provided, single submitter	clinical testing	Reported using alternate nomenclature G16S in the heterozygous state in a female with dysfibrinogenemia, however, segregation information was not included (Pietrys et al., 2011; Wypasek et al., 2019); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 28492530, 21725578, 27884173, 31479941, 27677677)
Mendelics	RCV002249738	SCV002517085	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Invitae	RCV001171744	SCV003245324	uncertain significance	not provided	2023-07-07	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 42 of the FGG protein (p.Gly42Ser). This variant is present in population databases (rs202132393, gnomAD 0.1%). This missense change has been observed in individual(s) with clinical features of FGG-related conditions (PMID: 21725578). ClinVar contains an entry for this variant (Variation ID: 900593). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002249738	SCV004222703	uncertain significance	not specified	2023-11-15	criteria provided, single submitter	clinical testing	Variant summary: FGG c.124G>A (p.Gly42Ser) results in a non-conservative amino acid change located in the 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. In addition, this variant disrupts the first nucleotide of exon 3, and therefore can affect splicing. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00042 in 242562 control chromosomes in the gnomAD database, including 2 homozygotes. However, the available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.124G>A has been reported in the literature in at least one heterozygous individual affected with symptomatic dysfibrinogenemia (e.g., Pietrys_2011, Wypasek_2019). This report does not provide unequivocal conclusions about association of the variant with Congenital Dysfibrinogenemia. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (e.g., Pietrys_2011). The following publications have been ascertained in the context of this evaluation (PMID: 21725578, 31479941). Five submitters have reported this variant to ClinVar after 2014 with conflicting assessments (VUS, n = 4; likely benign, n = 1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001171744	SCV001552642	uncertain significance	not provided		no assertion criteria provided	clinical testing	The FGG p.Gly42Ser variant was not identified in the literature nor was it identified in ClinVar, Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs202132393) and in control databases in 109 of 273944 chromosomes (2 homozygous) at a frequency of 0.000398, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Other in 10 of 7022 chromosomes (freq: 0.001424), Ashkenazi Jewish in 14 of 10212 chromosomes (freq: 0.001371), Latino in 26 of 34600 chromosomes (freq: 0.000751), European (non-Finnish) in 57 of 123364 chromosomes (freq: 0.000462) and African in 2 of 24438 chromosomes (freq: 0.000082), while the variant was not observed in the East Asian, European (Finnish) and South Asian populations. The p.Gly42 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The p.Gly42 variant occurs in the first base of the exon. This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. In addition, 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, RNA analysis has not been performed to confirm this prediction. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.