chr18-31598601-C-T

Position:

chr18-31598601-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM5BS2_Supporting

The NM_000371.4(TTR):c.370C>T(p.Arg124Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,614,076 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R124H) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

TTR
NM_000371.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:11

Conservation

PhyloP100: 3.43

Variant links:

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 links:

LOC124904277 (HGNC:):

LOC124904277 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

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

PM5

Other missense variant is known to change same aminoacid residue: Variant chr18-31598602-G-A is described in Lovd as [Pathogenic].

BS2

High AC in GnomAd4 at 7 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTR	NM_000371.4 linkuse as main transcript	c.370C>T	p.Arg124Cys	missense_variant	4/4	ENST00000237014.8	NP_000362.1
LOC124904277	XR_007066326.1 linkuse as main transcript	n.129-2906G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
TTR	ENST00000237014.8 linkuse as main transcript	c.370C>T	p.Arg124Cys	missense_variant	4/4	1	NM_000371.4	ENSP00000237014	P1
TTR	ENST00000649620.1 linkuse as main transcript	c.370C>T	p.Arg124Cys	missense_variant	6/6			ENSP00000497927	P1
TTR	ENST00000610404.5 linkuse as main transcript	c.274C>T	p.Arg92Cys	missense_variant	4/4	5		ENSP00000477599

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000517

AC:

AN:

251388

Hom.:

AF XY:

0.0000662

AC XY:

AN XY:

135866

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000435

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000226

AC:

AN:

1461874

Hom.:

Cov.:

AF XY:

0.0000330

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000227

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000385

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000378

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 30, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 24, 2024	Variant summary: TTR c.370C>T (p.Arg124Cys) results in a non-conservative amino acid change located in the Transthyretin/hydroxyisourate hydrolase domain (IPR023416) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.5e-05 in 1614076 control chromosomes, predominantly at a frequency of 0.00024 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 7.68 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTR causing Transthyretin Amyloidosis phenotype (3.1e-05). c.370C>T has been reported in the literature in individuals with clinical features of TTR-related contions (e.g., Saraiva_1999; Maurizi_2020). It has also been identified as a variant of uncertain significance in 6 individuals from a whole exome cohort with unclear phenotypes (e.g., Abouelhoda_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31371117, 10439123, 34380564). ClinVar contains an entry for this variant (Variation ID: 404412). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Blueprint Genetics	Feb 19, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 14, 2022	Identified in an individual with sensory axonal neuropathy in the published literature (Torres et al., 1996); Reported in a patient with cardiac amyloidosis (Maurizi et al., 2020) and a patient with CMT in the published literature (Volodarsky et al., 2021); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as Cys 104; This variant is associated with the following publications: (PMID: 31371117, 32376792, 33192475, 34380564, 35903975) -

Charcot-Marie-Tooth disease

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

- -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Nov 02, 2021

- -

Hyperthyroxinemia, dystransthyretinemic;C2751492:Amyloidosis, hereditary systemic 1;C5779776:Carpal tunnel syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 25, 2022

- -

Conduction disorder of the heart

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Oct 22, 2019

- -

Brugada syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Jan 17, 2019

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2022

The p.R124C variant (also known as c.370C>T), located in coding exon 4 of the TTR gene, results from a C to T substitution at nucleotide position 370. The arginine at codon 124 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration, which is also known as p.R104C, has been reported in a hypertrophic cardiomyopathy (HCM) cohort (Mazzarotto F et al. Genet Med, 2019 02;21:284-292; Maurizi N et al. Int J Cardiol, 2020 02;300:191-195). Additionally, this alteration was detected in an individual with neuropathy who was not found to have amyloid deposits in muscle or nerve biopsies, and an in vitro assay showed this alteration may not impact protein function (Grether NB et al. Ann Clin Transl Neurol, 2022 08;9:1252-1263). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Amyloidosis, hereditary systemic 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 22, 2023

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 124 of the TTR protein (p.Arg124Cys). This variant is present in population databases (rs745834030, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with cardiac amyloidosis and/or sensory axonal neuropathy (PMID: 10439123, 31371117). This variant is also known as Arg104Cys. ClinVar contains an entry for this variant (Variation ID: 404412). 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 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.012

BayesDel_noAF

Uncertain

0.080

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.89

D;D;T;.

Eigen

Benign

0.13

Eigen_PC

Benign

0.016

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.93

.;D;T;D

M_CAP

Pathogenic

0.30

MetaRNN

Uncertain

0.52

D;D;D;D

MetaSVM

Uncertain

0.46

MutationAssessor

Benign

0.81

L;L;.;.

MutationTaster

Benign

0.99

PrimateAI

Benign

0.25

PROVEAN

Benign

-2.3

.;N;.;.

REVEL

Uncertain

0.53

Sift

Pathogenic

0.0

.;D;.;.

Sift4G

Uncertain

0.0020

.;D;D;D

Polyphen

0.95

P;P;.;.

Vest4

0.32, 0.54, 0.35

MutPred

0.52

Loss of disorder (P = 0.0407);Loss of disorder (P = 0.0407);Loss of disorder (P = 0.0407);.;

MVP

0.98

MPC

1.6

ClinPred

0.32

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.32

gMVP

0.86

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over