18-31593026-G-C

Position:

• chr18-31593026-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 ENST00000237014.8(TTR):​c.200G>C​(p.Gly67Ala) 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 ENST00000237014.8 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• 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 ENST00000237014.8
• 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-A is described in ClinVar as [Pathogenic]. Clinvar id is 803481.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965
• PP5: Variant 18-31593026-G-C is Pathogenic according to our data. 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. Variant chr18-31593026-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.200G>C	p.Gly67Ala	missense_variant, splice_region_variant	2/4	ENST00000237014.8	NP_000362.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTR	ENST00000237014.8	c.200G>C	p.Gly67Ala	missense_variant, splice_region_variant	2/4	1	NM_000371.4	ENSP00000237014	P1

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:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2000	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 15, 2017	Variant summary: The TTR c.200G>C (p.Gly67Ala) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this substitution (SNPs&GO not captured due to low reliability index). This variant is absent in 121408 control chromosomes but was reported in several patients suggesting causality. Moreover, in at least two families the variant was observed to co-segregate with the disease further supporting a pathogenic outcome. Different variants affecting the same codon are listed in HGMD/ClinVar with a casual classification indicating the variant to be located in a mutational hotspot which supports the clinical relevance of the Gly67 residue. In addition, the p.Gly67Ala is found worldwide and has a high prevalence in German familial amyloid polyneuropathy patients (Niemietz_PlosOne_2016). Taken together, this variant is classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Athena Diagnostics

Mar 31, 2016

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 29, 2021

The p.G67A pathogenic mutation (also known as c.200G>C), located in coding exon 2 of the TTR gene, results from a G to C substitution at nucleotide position 200. The amino acid change results in glycine to alanine at codon 67, an amino acid with similar properties. This mutation, which is also known as p.G47A, was first reported in two unrelated Italian families with transthyretin (TTR) amyloidosis; both families presented with peripheral neuropathy and cardiomyopathy (Ferlini A et al. Hum. Mutat., 1994;4:61-4; Ferlini A et al. Clin. Genet., 2000 Apr;57:284-90). In a large cohort of families with TTR amyloidosis, this mutation was identified in 7 individuals from 2 unrelated families; 4 of these individuals had a mixed cardiac and neurologic phenotype and 3 of these individuals only had neurologic phenotype (Rapezzi C et al. Eur. Heart J., 2013 Feb;34:520-8). 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	0.25
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D;D;T;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.87	.;D;D;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Uncertain	2.2	M;M;.;.
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-4.7	.;D;.;.
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0060	.;D;.;.
Sift4G	Benign	0.25	.;T;D;D
Polyphen		0.98	D;D;.;.
Vest4		0.60, 0.61, 0.57
MutPred		0.82		Loss of catalytic residue at P63 (P = 0.1103);Loss of catalytic residue at P63 (P = 0.1103);Loss of catalytic residue at P63 (P = 0.1103);Loss of catalytic residue at P63 (P = 0.1103);
MVP		1.0
MPC		1.4
ClinPred		0.99	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
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;