Submissions for variant NM_021871.4(FGA):c.104G>A (p.Arg35His)

gnomAD frequency: 0.00001  dbSNP: rs121909607

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000851581	SCV000899295	pathogenic	Hypofibrinogenemia	2019-02-01	criteria provided, single submitter	research
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000851971	SCV000899410	pathogenic	Abnormal bleeding	2019-02-01	criteria provided, single submitter	research
Mayo Clinic Laboratories, Mayo Clinic	RCV001509236	SCV001715840	pathogenic	not provided	2024-07-10	criteria provided, single submitter	clinical testing	PM1, PM2_moderate, PM5, PS3, PS4_moderate
GeneDx	RCV001509236	SCV001874102	pathogenic	not provided	2024-04-09	criteria provided, single submitter	clinical testing	Published functional studies suggest a damaging effect: impaired thrombin polymerization, reduced fibrinogen clottability, reduced fibrinolysis velocity, and delayed release of fibrinopeptide A (PMID: 6830702, 22967385, 22880226); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (gnomAD); Also known as R16H using alternate nomenclature; This variant is associated with the following publications: (PMID: 32877852, 33822462, 33443927, 34275736, 32939696, 23962069, 22880226, 22967385, 6830702, 27684817, 6191801, 2738154, 9391726, 25320241, 26577257, 29070135, 29869737, 30856382, 31314131, 30332696, 32166693, 30349899, 2379562, 35949040, 35975558, 31064749, 3618591, 34455742, 7298640, 22169505)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002228034	SCV002511863	pathogenic	Familial dysfibrinogenemia	2022-04-08	criteria provided, single submitter	clinical testing	Variant summary: FGA c.104G>A (p.Arg35His) results in a non-conservative amino acid change in 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 1.2e-05 in 251286 control chromosomes (gnomAD). c.104G>A has been reported in the literature in multiple individuals affected with Congenital Dysfibrinogenemia (e.g. Simurda_2020, Szanto_2021, Zhou_2021), including at least one homozygote (Alving_1987). These data indicate that the variant is very likely to be associated with disease. Three ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic, and two as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Johns Hopkins Genomics, Johns Hopkins University	RCV002228034	SCV002570398	pathogenic	Familial dysfibrinogenemia	2022-07-11	criteria provided, single submitter	clinical testing	This FGA missense variant has been identified in the heterozygous state in multiple individuals with congenital dysfibrinogenemia, and is also reported in individuals with FGA-related congenital fibrinogen defects due to biallelic variants. This variant (rs121909607) is rare (<0.1%) in a large population dataset (gnomAD v2.1.1: 4/282670 total alleles; 0.0014%; no homozygotes). It has been reported in ClinVar7 (Variation ID 16404). Three bioinformatic tools queried predict that this substitution would be damaging, and the arginine residue at this position is evolutionarily conserved across all species assessed. Functional studies support that this missense change impacts protein function. We consider c.104G>A in FGA to be pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002476987	SCV002804033	pathogenic	Familial visceral amyloidosis, Ostertag type; Congenital afibrinogenemia; Familial dysfibrinogenemia	2024-01-30	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV002228034	SCV004175401	pathogenic	Familial dysfibrinogenemia	2022-08-29	criteria provided, single submitter	clinical testing	The FGA c.104G>A variant is classified as Pathogenic (PS1, PS4, PM1, PM2) The FGA c.104G>A variant is a single nucleotide change in exon 2/6 of the FGA gene, which is predicted to change the amino acid arginine at position 35 in the protein to histidine. The variant has been reported in probands with a clinical presentation of MIM: 616004 (PS4). The variant is rare in population databases (gnomAD allele frequency = 0.0013%; 2 het and 0 hom in 152172 sequenced alleles; highest frequency = 0.0024%, African/African American population) (PM2). Detected in 7x patients with disease in PMID 31064749. This variant is located in a conserved region (PM1). (PMID:34275736) This variant results in the same amino acid change as a previously established variant (PS1). The variant has been reported in dbSNP (rs121909607) and has been reported as Pathogenic/Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 16404). It has not been reported in HGMD.
OMIM	RCV000030941	SCV000038124	pathogenic	Dysfibrinogenemia	1989-07-01	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004532379	SCV004117662	pathogenic	FGA-related disorder	2024-05-28	no assertion criteria provided	clinical testing	The FGA c.104G>A variant is predicted to result in the amino acid substitution p.Arg35His. This variant, also referred to as p.Arg16His using legacy nomenclature, has been reported in many patients to be causative for autosomal dominant congenital dysfibrinogenemia (Casini et al. 2015. PubMed ID: 25320241; Siebenlist et al. 1988. PubMed ID: 3345340; Smith et al. 2018. PubMed ID: 30349899; Shapiro et al. 2013. PubMed ID: 23061815). Other missense variants affecting this amino acid (p.Arg35Cys, p.Arg35Ser, p.Arg35Pro) have also been reported in patients with dysfibrinogenemia, suggesting p.Arg35 is important for proper FGA protein function (Miesbach et al. 2010. PubMed ID: 19923982; Shapiro et al. 2013. PubMed ID: 23061815). This variant is reported in 0.0031% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.