18-31595129-T-G

Variant names:

• chr18-31595129-T-G
• rs121918076
• NM_000371.4:c.210T>G

Variant summary

Our verdict is Pathogenic. The variant received 24 ACMG points: 24P and 0B. PS1_Very_Strong PM1 PM2 PM5 PP2 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 the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S70G) has been classified as Likely 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
• Publications: 22 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 24 ACMG points.

• PS1: Transcript NM_000371.4 (TTR) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 32 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 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 chr18-31595127-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2169601.
• 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: 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 VariationId is 13429.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000371.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTR	NM_000371.4	MANE Select	c.210T>G	p.Ser70Arg	missense	Exon 3 of 4	NP_000362.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTR	ENST00000237014.8	TSL:1 MANE Select	c.210T>G	p.Ser70Arg	missense	Exon 3 of 4	ENSP00000237014.4
	TTR	ENST00000649620.1		c.210T>G	p.Ser70Arg	missense	Exon 5 of 6	ENSP00000497927.1
	TTR	ENST00000610404.5	TSL:5	c.114T>G	p.Ser38Arg	missense	Exon 3 of 4	ENSP00000477599.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Amyloidosis, hereditary systemic 1 Pathogenic:3

Apr 03, 2015

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Oct 01, 1992

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Dec 15, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (ExAC no frequency). 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). 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"). 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. For these reasons, this variant has been classified as Pathogenic. 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.

not provided Pathogenic:1

Mar 07, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1, PM1, PM2, PS1, PS4

Cardiovascular phenotype Pathogenic:1

Jul 05, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

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
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.13	N
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		-0.017
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.9	N
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.025	D
Polyphen		0.95	P
Vest4		0.52
MutPred		0.66		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
Mutation Taster		=26/74	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121918076; hg19: chr18-29175092;