Submissions for variant NM_021870.3(FGG):c.571G>A (p.Gly191Arg)

gnomAD frequency: 0.00339  dbSNP: rs6063

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000851827	SCV000899811	uncertain significance	Hypofibrinogenemia	2019-02-01	criteria provided, single submitter	research
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000791084	SCV000930354	uncertain significance	not specified	2019-04-27	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000963143	SCV001110279	likely benign	not provided	2024-01-18	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001144043	SCV001304618	benign	Congenital afibrinogenemia	2017-04-27	criteria provided, single submitter	clinical testing	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). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV002222000	SCV002499578	uncertain significance	Familial dysfibrinogenemia		criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000963143	SCV004151193	likely benign	not provided	2023-02-01	criteria provided, single submitter	clinical testing	FGG: BS2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000791084	SCV005185036	likely benign	not specified	2024-05-22	criteria provided, single submitter	clinical testing	Variant summary: FGG c.571G>A (p.Gly191Arg) results in a non-conservative amino acid change located in the Fibrinogen, alpha/beta/gamma chain, C-terminal globular domain (IPR002181) 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 0.0028 in 251212 control chromosomes in the gnomAD database, including 3 homozygotes. c.571G>A has been reported in the literature in individuals affected with thrombotic disorder or HELLP syndrome without evidence of causality (e.g. Downes_2019, Jimenez_2020). These reports do not provide unequivocal conclusions about association of the variant with Congenital Dysfibrinogenemia. 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: 31064749, 33059327). ClinVar contains an entry for this variant (Variation ID: 16378). Based on the evidence outlined above, the variant was classified as likely benign.
OMIM	RCV000017800	SCV000038079	pathogenic	Fibrinogen Milano XII, digenic	2001-07-15	no assertion criteria provided	literature only
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000963143	SCV001554313	uncertain significance	not provided		no assertion criteria provided	clinical testing	The FGG p.Gly191Arg variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs6063) as "With Pathogenic allele" and in ClinVar (variant classified as pathogenic by OMIM; associated condition is digenic Fibrinogen Milano XII) The variant was identified in control databases in 784 of 282600 chromosomes (4 homozygous) at a frequency of 0.002774 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 596 of 128994 chromosomes (freq: 0.00462), Ashkenazi Jewish in 39 of 10360 chromosomes (freq: 0.003764), Other in 26 of 7216 chromosomes (freq: 0.003603), Latino in 85 of 35390 chromosomes (freq: 0.002402), African in 23 of 24960 chromosomes (freq: 0.000922), European (Finnish) in 11 of 25120 chromosomes (freq: 0.000438) and South Asian in 4 of 30610 chromosomes (freq: 0.000131), while the variant was not observed in the and East Asian population. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Gly191 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, BLOSUM, MutationTaster) suggest that the G variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. 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.