rs121918090

Variant names:

• chr18-31593026-G-A
• rs121918090
• NM_000371.4:c.200G>A

Your query was ambiguous. Multiple possible variants found:

• chr18-31593026-G-A
• chr18-31593026-G-C
• chr18-31593026-G-T

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate 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:4
• Conservation: PhyloP100: 5.86
• Publications: 14 publications found

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]

TTR Gene-Disease associations (from GenCC):

• amyloidosis, hereditary systemic 1

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• familial amyloid neuropathy

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hereditary ATTR amyloidosis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• heart conduction disease

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• ATTRV122I amyloidosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PM1: In a hotspot region, there are 30 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 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 chr18-31593025-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 13459.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 108 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 1.0149 (below the threshold of 3.09). Trascript score misZ: 1.5458 (below the threshold of 3.09). GenCC associations: The gene is linked to familial amyloid neuropathy, amyloidosis, hereditary systemic 1, ATTRV122I amyloidosis, hereditary ATTR amyloidosis, heart conduction disease.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 18-31593026-G-A is Pathogenic according to our data. Variant chr18-31593026-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 803481.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTR	NM_000371.4	c.200G>A	p.Gly67Glu	missense_variant, splice_region_variant	Exon 2 of 4	ENST00000237014.8	NP_000362.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTR	ENST00000237014.8	c.200G>A	p.Gly67Glu	missense_variant, splice_region_variant	Exon 2 of 4	1	NM_000371.4	ENSP00000237014.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Amyloidosis, hereditary systemic 1 Pathogenic:3

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (PMID: 12000196, 20209591; internal data). This variant is also known as p.Gly47Glu. ClinVar contains an entry for this variant (Variation ID: 803481). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

May 28, 2019

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 04, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TTR c.200G>A (p.Gly67Glu) results in a non-conservative amino acid change located in the Transthyretin domain (IPR023416) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251660 control chromosomes. c.200G>A has been reported in the literature in multiple individuals affected with Transthyretin Amyloidosis (e.g. Pelo_2002, Haagsma_2004, Lachmann_2002, Rapezzi_2013, Labcorp (formerly Invitae)). These data indicate that the variant is very likely to be associated with disease. Multiple different variants located at the same codon (p.Gly67Ala, p.Gly67Val) have been classified as pathogenic by our lab supporting a critical relevance of this residue to TTR protein function. The following publications have been ascertained in the context of this evaluation (PMID: 22745357, 15185498, 12050338, 12000196). ClinVar contains an entry for this variant (Variation ID: 803481). Based on the evidence outlined above, the variant was classified as pathogenic. -

Cardiovascular phenotype Pathogenic:1

Sep 24, 2014

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
LIST_S2	Benign	0.85	.;T;T;T
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;.;.
PhyloP100		5.9
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-6.3	.;D;.;.
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	.;D;.;.
Sift4G	Uncertain	0.024	.;D;D;D
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
Mutation Taster		=3/97	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121918090; hg19: chr18-29172989; COSMIC: COSV52701600;