18-31593026-G-T

Variant names:

• chr18-31593026-G-T
• rs121918090
• NM_000371.4:c.200G>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>T​(p.Gly67Val) 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 Likely 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/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• 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-T is Pathogenic according to our data. Variant chr18-31593026-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 938206.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>T	p.Gly67Val	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>T	p.Gly67Val	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/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Amyloidosis, hereditary systemic 1 Pathogenic:2

Feb 13, 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>T (p.Gly67Val) results in a non-conservative amino acid change located in the Transthyretin/hydroxyisourate hydrolase 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 251460 control chromosomes (gnomAD). c.200G>T has been reported in the literature in multiple individuals affected with Transthyretin Amyloidosis (Gillmore_2015, Gillmore_2016, Low_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26243339, 27143678, 34059423). ClinVar contains an entry for this variant (Variation ID: 938206). Based on the evidence outlined above, the variant was classified as pathogenic.

Jun 20, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Gly67 amino acid residue in TTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20209591, 12000196). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individuals affected with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (PMID: 7599630, 25997029, 26986100). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with valine at codon 67 of the TTR protein (p.Gly67Val). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and valine. This variant also falls at the last nucleotide of exon 2 of the TTR coding sequence, which is part of the consensus splice site for this exon.

Cardiovascular phenotype Pathogenic:1

Apr 03, 2019

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.200G>T pathogenic mutation (also known as p.G67V), located in coding exon 2 of the TTR gene, results from a G to T substitution at nucleotide position 200. The amino acid change results in glycine to valine at codon 67, an amino acid with dissimilar properties. However, this change occurs in the last base pair of coding exon 2, which makes it likely to have some effect on normal mRNA splicing. This variant was detected in multiple individuals with TTR-related amyloidosis (Saraiva MJ. Hum. Mutat., 1995;5:191-6; Suenaga G et al. Sci Rep, 2017 05;7:1579). Different alterations at this same position (c.200G>C G67A, c.200G>A G67E) have been reported in multiple individuals with TTR-related amyloidosis (Ferlini A et al. Hum. Mutat., 1994;4:61-4; Pelo E et al. Amyloid, 2002 Mar;9:35-41; Barreiros AP et al. Liver Transpl., 2010 Mar;16:314-23; Rapezzi C et al. Eur. Heart J., 2013 Feb;34:520-8). 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	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;D;T;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.0	.;D;D;D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	M;M;.;.
PhyloP100		5.9
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	0.0	.;D;.;.
REVEL	Benign	0.0
Sift	Pathogenic	0.0	.;D;.;.
Sift4G	Pathogenic	0.0	.;T;D;D
Vest4		0.0
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.98
Mutation Taster		=5/95	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.88
SpliceAI score (max)		0.070		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;