rs121918076

Positions:

• chr18-31595129-T-A
• chr18-31595129-T-C
• chr18-31595129-T-G

Variant summary

Our verdict is Pathogenic. Variant got 23 ACMG points: 23P and 0B. PS1_Very_Strong PM1 PM2 PM5 PP3 PP5_Very_Strong

The ENST00000237014.8(TTR):​c.210T>A​(p.Ser70Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S70I) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TTR ENST00000237014.8 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: -0.0170

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 23 ACMG points.

• PS1: Transcript ENST00000237014.8 (TTR) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 13429
• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 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 chr18-31595127-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2169601.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.784
• PP5: Variant 18-31595129-T-A is Pathogenic according to our data. Variant chr18-31595129-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 36890.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTR	NM_000371.4	c.210T>A	p.Ser70Arg	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.210T>A	p.Ser70Arg	missense_variant	3/4	1	NM_000371.4	ENSP00000237014	P1
TTR	ENST00000649620.1	c.210T>A	p.Ser70Arg	missense_variant	5/6			ENSP00000497927	P1
TTR	ENST00000610404.5	c.114T>A	p.Ser38Arg	missense_variant	3/4	5		ENSP00000477599
TTR	ENST00000541025.2	n.236T>A		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Amyloidosis, hereditary systemic 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 29, 2016	Variant summary: The TTR c.210T>A (p.Ser70Arg) variant involves the alteration of a non-conserved nucleotide. Ser70 is located in the Transthyretin/hydroxyisourate hydrolase, superfamily domain and p.Ser70Ile has been classified as pathogenic by our laboratory, indicateing Ser70 is critical for TTR function. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in 120430 control chromosomes. This variant has been reported in numerous ATTR patients. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 70 of the TTR protein (p.Ser70Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with transthyretin amyloidosis (PMID: 22745357, 22928869, 23317988, 23713495, 24053266). It is commonly reported in individuals of Mexico ancestry (PMID: 22745357, 22928869, 23317988, 23713495, 24053266). This variant is also known as in other populations (PMID: 22745357, 22928869, 23317988, 23713495, 24053266). ClinVar contains an entry for this variant (Variation ID: 36890). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Athena Diagnostics

Dec 14, 2020

This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In some published literature, this variant is referred to as Ser50Arg. This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant affects the stability and function of the protein (PMID: 12874858, 17503405). -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 24, 2018

The p.S70R pathogenic mutation (also known as c.210T>A and S50R), located in coding exon 3 of the TTR gene, results from a T to A substitution at nucleotide position 210. The serine at codon 70 is replaced by arginine, an amino acid with dissimilar properties. This mutation has been described in numerous unrelated families of Japanese, Caucasian, and Mexican ancestry with familial amyloid polyneuropathy (Ueno S et al. Biochem. Biophys. Res. Commun. 1990 Jun;169(3):1117-21; Munar-Qués M et al. Amyloid 2007 Jun;14(2):147-52; González-Duarte A et al. Amyloid 2013 Dec;20(4):221-5). Of note, the nucleotide changes observed in these studies, which all result in the same p.S70R amino acid substitution, include c.210T>G, c.208A>C, and c.210T>A, respectively. In one Italian study, three of four individuals from two unrelated families with this mutation were observed to have a mixed neurologic and cardiac phenotype, while one individual had a primarily neurologic phenotype (Rapezzi C et al. Eur. Heart J. 2013 Feb; 34(7):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	Uncertain	0.52
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;D;T;.
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.11	N
LIST_S2	Uncertain	0.86	.;D;D;T
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.78	D;D;D;D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Uncertain	2.1	M;M;.;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.9	.;N;.;.
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0090	.;D;.;.
Sift4G	Uncertain	0.025	.;D;T;D
Polyphen		0.95	P;P;.;.
Vest4		0.52, 0.61, 0.96
MutPred		0.66		Loss of glycosylation at S70 (P = 0.0143);Loss of glycosylation at S70 (P = 0.0143);Loss of glycosylation at S70 (P = 0.0143);Loss of glycosylation at S70 (P = 0.0143);
MVP		0.99
MPC		0.90
ClinPred		0.92	D
GERP RS		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.75
gMVP		0.94

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

LitVar

Other links and lift over

dbSNP: rs121918076; hg19: chr18-29175092;