Submissions for variant NM_000371.4(TTR):c.325G>C (p.Glu109Gln)

dbSNP: rs121918082

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000236028	SCV000293408	pathogenic	not provided	2019-07-18	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23193944, 24073013, 27238058, 27858761, 21692911, 25408161, 28508289, 28635949, 26959691, 24767411, 16530227, 15110620, 9748569, 30328212, 28188196, 29048471, 30981840, 23713495, 12771895, 1301926, 22745357, 31353960, 31371117, 31826067, 31517333, 32740500, 26656838)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000014384	SCV000696627	pathogenic	Familial amyloid neuropathy	2017-07-13	criteria provided, single submitter	clinical testing	Variant summary: The TTR c.325G>C (p.Glu109Gln) variant involves the alteration of a conserved nucleotide, resulting in a missense change within the transthyretin/hydroxyisourate hydrolase domain (InterPro). 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent from the large control database ExAC (0/121328 control chromosomes). The variant has been identified in numerous heterozygous patients and families with transthyretin amyloidosis (e.g., Wixner_OJRD_2014; Nardo_TP_2004; Durmus-Tekce_Neuromusc Dis_2016). Overlapping and nearby disease-associated mutations such as E109K, H108R, H110N and H110D suggest the residue and the motif are critical for proper protein function. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000236028	SCV001245842	pathogenic	not provided	2018-05-01	criteria provided, single submitter	clinical testing
Invitae	RCV000014384	SCV001392545	pathogenic	Familial amyloid neuropathy	2022-05-25	criteria provided, single submitter	clinical testing	This variant disrupts the p.Glu109 amino acid residue in TTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10842705, 20209591, 25644864, 28911993). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. 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 TTR protein function. ClinVar contains an entry for this variant (Variation ID: 13442). This variant is also known as p.Glu89Gln (E89Q). This missense change has been observed in individuals with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) and hATTR amyloidosis (PMID: 1301926, 28635949). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 109 of the TTR protein (p.Glu109Gln).
Ambry Genetics	RCV002321480	SCV002606916	pathogenic	Cardiovascular phenotype	2022-09-26	criteria provided, single submitter	clinical testing	The p.E109Q pathogenic mutation (also known as c.325G>C), located in coding exon 3 of the TTR gene, results from a G to C substitution at nucleotide position 325. The glutamic acid at codon 109 is replaced by glutamine, an amino acid with highly similar properties. This alteration, which is also known as p.E89Q, was first described in an Italian family with hereditary transthyretin (TTR)-related amyloidosis (Almeida MR et al. Hum Mutat. 1992;1(3):211-5). This alteration is the most common TTR mutation in the Italian population and is associated with a mixed phenotype (Coelho T et al. Curr Med Res Opin. 2013;29(1):63-76; Rapezzi C. et al. Eur Heart J. 2013;34(7):520-8, Castaño A, et al. Heart Fail Rev 2015 Mar; 20(2):163-78). In addition, another mutation at the same position, p.E109K, has also been described in individuals with hereditary TTR-related amyloidosis (Barreiros AP, et al. Liver Transpl. 2010;16(3):314-23), Rapezzi C, et al. Eur. Heart J. 2013;34(7):520-8). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by BayesDel in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Athena Diagnostics	RCV000236028	SCV004229421	pathogenic	not provided	2022-10-15	criteria provided, single submitter	clinical testing	This variant has been identified in multiple unrelated individuals with clinical features associated with hereditary transthyretin-related amyloidosis and familial carpal tunnel syndrome and segregates with disease in multiple families. This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). In some published literature, this variant is referred to as p.Glu89Gln.
OMIM	RCV000014384	SCV000034633	pathogenic	Familial amyloid neuropathy	1992-01-01	no assertion criteria provided	literature only
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	RCV000014384	SCV002754560	likely pathogenic	Familial amyloid neuropathy	2022-02-02	no assertion criteria provided	clinical testing