18-31595129-T-G

Position:

• chr18-31595129-T-G

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PS1 PM1 PM2 PM5 PP3 PP5_Very_Strong

The NM_000371.4(TTR):​c.210T>G​(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 Lovd. 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 NM_000371.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• 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]

TTR (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PS1: Transcript NM_000371.4 (TTR) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM1: In a chain Transthyretin (size 126) in uniprot entity TTHY_HUMAN there are 141 pathogenic changes around while only 6 benign (96%) 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 chr18-31595128-G-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.782
• PP5: Variant 18-31595129-T-G is Pathogenic according to our data. Variant chr18-31595129-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 13429.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-31595129-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Amyloidosis, hereditary systemic 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 15, 2018	For these reasons, this variant has been classified as Pathogenic. A different variant (c.210T>A) giving rise to the same protein effect observed here (p.Ser70Arg) has been determined to be pathogenic (PMID: 24053266, 22745357, 22928869). This suggests that this variant is also likely to be causative of disease. 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: "Possibly Damaging"; Align-GVGD: "Class Class C0"). This variant has been observed in several individuals with amyloidosis (PMID: 23713495, 1335038, 2363717, 27273296).  This variant is also known as p.Ser50Arg in the literature. ClinVar contains an entry for this variant (Variation ID: 13429). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with arginine at codon 70 of the TTR protein (p.Ser70Arg). The serine residue is weakly conserved and there is a moderate physicochemical difference between serine and arginine. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 1992	- -
Pathogenic, no assertion criteria provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 03, 2015	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Mar 07, 2023

PP1, PM1, PM2, PS1, PS4 -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 05, 2022

The p.S70R pathogenic mutation (also known as c.210T>G and S50R), located in coding exon 3 of the TTR gene, results from a T to G 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). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	0.13	N
LIST_S2	Uncertain	0.86	.;D;D;T
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.78	D;D;D;D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Uncertain	2.1	M;M;.;.
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
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;