rs121918075

Positions:

• chr18-31598632-A-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000371.4(TTR):​c.401A>G​(p.Tyr134Cys) 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. Y134H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TTR NM_000371.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 0.529

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]

LOC124904277 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 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 chr18-31598631-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 13449.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• PP5: Variant 18-31598632-A-G is Pathogenic according to our data. Variant chr18-31598632-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 13419.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-31598632-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTR	NM_000371.4	c.401A>G	p.Tyr134Cys	missense_variant	4/4	ENST00000237014.8
LOC124904277	XR_007066326.1	n.129-2937T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTR	ENST00000237014.8	c.401A>G	p.Tyr134Cys	missense_variant	4/4	1	NM_000371.4	P1
TTR	ENST00000649620.1	c.401A>G	p.Tyr134Cys	missense_variant	6/6			P1
TTR	ENST00000610404.5	c.305A>G	p.Tyr102Cys	missense_variant	4/4	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial amyloid neuropathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 22, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TTR function (PMID: 15820680, 21135536). 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. ClinVar contains an entry for this variant (Variation ID: 13419). This variant is also known as Tyr114Cys or Y114C. This missense change has been observed in individuals with amyloidosis (PMID: 2161654, 21135536, 23713495). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 134 of the TTR protein (p.Tyr134Cys). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 1992	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 26, 2020

Published functional studies demonstrate that this variant has a damaging effect on the TTR protein (Zhang et al., 2011; Li et al., 2014); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; The Y134C is also reported as Y114C in the published literature; This variant is associated with the following publications: (PMID: 26656838, 16217058, 21135536, 25382970, 31782077, 32353608, 31718691, 1330202, 27859927, 28943540, 2161654, 17503405, 15820680, 22620962, 23713495) -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 25, 2023

The c.401A>G (p.Y134C) alteration is located in exon 4 (coding exon 4) of the TTR gene. This alteration results from an A to G substitution at nucleotide position 401, causing the tyrosine (Y) at amino acid position 134 to be replaced by a cysteine (C). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant (also referenced as p.Y114C) has been reported in the heterozygous state in multiple individuals with features consistent with adult-onset hereditary transthyretin-related amyloidosis and co-segregates with disease in several families (Du, 2021; Yamashita, 2019; Koike, 2018; Misumi, 2016; Ihse, 2013; Zhuang, 2022; Nakamura, 2005; Ueno, 1992; Ueno, 1990). Additionally, other missense variants at the same amino acid position, c.400T>C (p.Y134H) and c.401A>C (p.Y134S), have been described in individuals with features consistent with hereditary transthyretin-related amyloidosis (Matsushima, 2023; Nakase, 2019). This amino acid position is not well conserved in available vertebrate species. Based on internal structural analysis, this variant is anticipated to result in a decrease in structural stability (Wojtczak, 1996). In vitro functional studies indicate this alteration reduces TTR stability, alters oligomerization, and contributes to cytotoxicity (Sekijima, 2005; Zhang, 2011; Li, 2014). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;D;T;.
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.74	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.8	H;H;.;.
MutationTaster	Benign	1.0	A
PrimateAI	Benign	0.47	T
Polyphen		1.0	D;D;.;.
Vest4		0.61, 0.75, 0.77
MutPred		0.91		Gain of catalytic residue at P133 (P = 0.016);Gain of catalytic residue at P133 (P = 0.016);.;.;
MVP		1.0
MPC		0.82
ClinPred		0.79	D
GERP RS		-1.3
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
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: rs121918075; hg19: chr18-29178595;