chr18-31595244-G-A

Position:

• chr18-31595244-G-A

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS1_Moderate PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000371.4(TTR):​c.325G>A​(p.Glu109Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E109Q) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TTR NM_000371.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• 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 20 ACMG points.

• PS1: Transcript NM_000371.4 (TTR) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• 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 chr18-31595244-G-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973
• PP5: Variant 18-31595244-G-A is Pathogenic according to our data. Variant chr18-31595244-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1073324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-31595244-G-A is described in Lovd as [Pathogenic]. Variant chr18-31595244-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTR	NM_000371.4	c.325G>A	p.Glu109Lys	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>A	p.Glu109Lys	missense_variant	3/4	1	NM_000371.4	ENSP00000237014	P1
TTR	ENST00000649620.1	c.325G>A	p.Glu109Lys	missense_variant	5/6			ENSP00000497927	P1
TTR	ENST00000610404.5	c.229G>A	p.Glu77Lys	missense_variant	3/4	5		ENSP00000477599
TTR	ENST00000541025.2	n.351G>A		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461868 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 02, 2021	The TTR c.325G>A; p.Glu109Lys variant, also known as p.Glu89Lys, is reported in the literature in multiple individuals affected with hereditary transthyretin amyloidosis (ATTR, Nakamura 2000, Reynolds 2017, Rapezzi 2013, Suhr 2016). This variant is also reported in ClinVar (Variation ID: 1073324) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Additionally, other variants at this codon (c.325G>C, p.Glu109Lys; c.327G>T, p.Glu109Asp) have been reported in individuals with ATTR and are considered pathogenic (Chao 2019, Reynolds 2017). The glutamic acid at codon 109 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.767). Based on available information, this variant is considered to be likely pathogenic. References: Chao HC et al. Clinical and genetic profiles of hereditary transthyretin amyloidosis in Taiwan. Ann Clin Transl Neurol. 2019 Apr 9;6(5):913-922. PMID: 31139689. Nakamura M et al. A novel variant of transthyretin (Glu89Lys) associated with familial amyloidotic polyneuropathy. Amyloid. 2000 Mar;7(1):46-50. PMID: 10842705. Reynolds MM et al. Ocular Manifestations of Familial Transthyretin Amyloidosis. Am J Ophthalmol. 2017 Nov;183:156-162. PMID: 28911993. Rapezzi C et al. Disease profile and differential diagnosis of hereditary transthyretin-related amyloidosis with exclusively cardiac phenotype: an Italian perspective. Eur Heart J. 2013 Feb;34(7):520-8. PMID: 22745357. Suhr OB et al. Survival After Transplantation in Patients With Mutations Other Than Val30Met: Extracts From the FAP World Transplant Registry. Transplantation. 2016 Feb;100(2):373-81. PMID: 26656838. -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Amyloidosis, hereditary systemic 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 09, 2023	For these reasons, this variant has been classified as Pathogenic. 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: 1301926, 28635949). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 1073324). This variant is also known as Glu89Lys. This missense change has been observed in individual(s) with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (PMID: 10842705, 20209591, 25644864, 26428663, 28911993). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 109 of the TTR protein (p.Glu109Lys). -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.77; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV001073324 ) and a different missense change at the same codon (p.Glu109Gln / ClinVar ID: VCV000013442 ) have been previously reported as pathogenic/likely pathogenic with strong evidence. Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 21, 2021

The p.E109K pathogenic mutation (also known as c.325G>A), located in coding exon 3 of the TTR gene, results from a G to A substitution at nucleotide position 325. The glutamic acid at codon 109 is replaced by lysine, an amino acid with similar properties. This mutation (also referred to as and E89K) has been detected in several individuals from hereditary transthyretin amyloidosis and familial amyloid polyneuropathy cohorts including individuals with polyneuropathy, cardiac involvement or mixed phenotype (Barreiros AP, et al. Liver Transpl. 2010;16(3):314-23; Rapezzi C, et al. Eur. Heart J. 2013;34(7):520-8; Choi K et al. J Clin Neurol. 2018 Oct;14(4):537-541; Gawor M et al. Cardiol J, 2020 Aug [online ahead of print]). This mutation was also reported to segregate with disease in a family (Jang MA et al. Ann Hum Genet, 2015 Mar;79:99-107). In addition, another mutation at the same position (p.E109Q, c.325G>C) has also been reported in association with hereditary transthyretin amyloidosis (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). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by 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	0.27
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D;D;T;.
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	.;D;D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.3	M;M;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.5	.;N;.;.
REVEL	Pathogenic	0.77
Sift	Benign	0.040	.;D;.;.
Sift4G	Benign	0.19	.;T;D;T
Polyphen		0.98	D;D;.;.
Vest4		0.67, 0.65, 0.68
MutPred		0.83		Gain of methylation at E109 (P = 0.0068);Gain of methylation at E109 (P = 0.0068);Gain of methylation at E109 (P = 0.0068);Gain of methylation at E109 (P = 0.0068);
MVP		1.0
MPC		1.3
ClinPred		0.95	D
GERP RS		5.7
Varity_R		0.89
gMVP		0.95

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-29175207;