rs121918090

chr18-31593026-G-Achr18-31593026-G-Cchr18-31593026-G-T

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.200G>A(p.Gly67Glu) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G67R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TTR NM_000371.4 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.86

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 hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain 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 chr18-31593026-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 13451.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 18-31593026-G-A is Pathogenic according to our data. Variant chr18-31593026-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 803481.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-31593026-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTR	NM_000371.4	c.200G>A	p.Gly67Glu	missense_variant, splice_region_variant	2/4	ENST00000237014.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTR	ENST00000237014.8	c.200G>A	p.Gly67Glu	missense_variant, splice_region_variant	2/4	1	NM_000371.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial amyloid neuropathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 22, 2022	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the c.200G nucleotide in the TTR gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 26986100; Invitae). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). ClinVar contains an entry for this variant (Variation ID: 803481). This variant is also known as p.Gly47Glu. This missense change has been observed in individual(s) with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (PMID: 12000196, 20209591; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 67 of the TTR protein (p.Gly67Glu). This variant also falls at the last nucleotide of exon 2, which is part of the consensus splice site for this exon. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 24, 2014

The p.G67E pathogenic mutation (also known as c.200G>A and G47E), located in coding exon 2 of the TTR gene, results from a G to A substitution at nucleotide position 200. The amino acid change results in glycine to glutamic acid at codon 67. This change occurs in the last base pair of exon 2 which makes it likely to have some effect on normal mRNA splicing; however, direct evidence is not available. Two disease-causing mutations, p.G67A and p.G67R, have been described in the same codon. This pathogenic mutation was first identified in two siblings presenting in their late third decade with peripheral neuropathy, autonomic dysfunction and a family history consistent with familial amyloid polyneuropathy; there was rapid progression of disease in this family along with anticipation in the age of onset of symptoms (Pelo E et al. Amyloid. 2002;9(1):35-41). A functional study found this mutation lead to decreased conformational stability (Altland K et al. Electrophoresis. 2007;28(12):2053-64). An additional study identified this mutation in two unrelated individuals presenting with predominantly neurologic symptoms in their fourth decade; both patients had symptoms of renal impairment, motoric, sensoric, and autonomic polyneuropathy and one patient additionally had restrictive cardiac function (Barreiros AP et al. Liver Transpl. 2010;16(3):314-23). Based on the supporting evidence, p.G67E is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
Cadd	Pathogenic	33
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;D;T;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.85	D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	M;M;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.60	T
Polyphen		1.0	D;D;.;.
Vest4		0.69, 0.73, 0.76
MutPred		0.85		Gain of disorder (P = 0.1092);Gain of disorder (P = 0.1092);Gain of disorder (P = 0.1092);Gain of disorder (P = 0.1092);
MVP		1.0
MPC		1.6
ClinPred		0.99	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.91
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: rs121918090; hg19: chr18-29172989; COSMIC: COSV52701600;