18-31595244-G-C

Position:

• chr18-31595244-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000371.4(TTR):​c.325G>C​(p.Glu109Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E109K) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TTR NM_000371.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 3.64

Genes affected

TTR (HGNC:12405): (transthyretin) This gene encodes one of the three prealbumins, which include alpha-1-antitrypsin, transthyretin and orosomucoid. The encoded protein, transthyretin, is a homo-tetrameric carrier protein, which transports thyroid hormones in the plasma and cerebrospinal fluid. It is also involved in the transport of retinol (vitamin A) in the plasma by associating with retinol-binding protein. The protein may also be involved in other intracellular processes including proteolysis, nerve regeneration, autophagy and glucose homeostasis. Mutations in this gene are associated with amyloid deposition, predominantly affecting peripheral nerves or the heart, while a small percentage of the gene mutations are non-amyloidogenic. The mutations are implicated in the etiology of several diseases, including amyloidotic polyneuropathy, euthyroid hyperthyroxinaemia, amyloidotic vitreous opacities, cardiomyopathy, oculoleptomeningeal amyloidosis, meningocerebrovascular amyloidosis and carpal tunnel syndrome. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a chain Transthyretin (size 126) in uniprot entity TTHY_HUMAN there are 141 pathogenic changes around while only 6 benign (96%) in NM_000371.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.952
• PP5: Variant 18-31595244-G-C is Pathogenic according to our data. Variant chr18-31595244-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 13442.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-31595244-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTR	NM_000371.4	c.325G>C	p.Glu109Gln	missense_variant	3/4	ENST00000237014.8	NP_000362.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTR	ENST00000237014.8	c.325G>C	p.Glu109Gln	missense_variant	3/4	1	NM_000371.4	ENSP00000237014	P1
TTR	ENST00000649620.1	c.325G>C	p.Glu109Gln	missense_variant	5/6			ENSP00000497927	P1
TTR	ENST00000610404.5	c.229G>C	p.Glu77Gln	missense_variant	3/4	5		ENSP00000477599
TTR	ENST00000541025.2	n.351G>C		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Amyloidosis, hereditary systemic 1 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 25, 2022	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). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1992	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	Feb 02, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 13, 2017	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. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 15, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 18, 2019	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) -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 26, 2022

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.78	D;D;T;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.87	.;D;D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Benign	1.9	L;L;.;.
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.94	.;N;.;.
REVEL	Uncertain	0.63
Sift	Benign	0.14	.;T;.;.
Sift4G	Benign	0.20	.;T;T;T
Polyphen		0.70	P;P;.;.
Vest4		0.41, 0.47, 0.74
MutPred		0.82		Loss of glycosylation at S105 (P = 0.3143);Loss of glycosylation at S105 (P = 0.3143);Loss of glycosylation at S105 (P = 0.3143);Loss of glycosylation at S105 (P = 0.3143);
MVP		1.0
MPC		0.80
ClinPred		0.72	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.77
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121918082; hg19: chr18-29175207;