rs745834030

chr18-31598601-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM5 BS2

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 Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: TTR NM_000371.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:11
• Conservation: PhyloP100: 3.43

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 Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain 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 GnomAd at 7 AD gene.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTR	ENST00000237014.8	c.370C>T	p.Arg124Cys	missense_variant	4/4	1	NM_000371.4	P1
TTR	ENST00000649620.1	c.370C>T	p.Arg124Cys	missense_variant	6/6			P1
TTR	ENST00000610404.5	c.274C>T	p.Arg92Cys	missense_variant	4/4	5

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152202 Hom.: 0 Cov.: 33

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: 13 AN: 251388 Hom.: 1 AF XY: 0.0000662 AC XY: 9 AN XY: 135866

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: 33 AN: 1461874 Hom.: 0 Cov.: 31 AF XY: 0.0000330 AC XY: 24 AN XY: 727240

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: 7 AN: 152202 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74360

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: 5

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 15, 2021	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 5.2e-05 in 251388 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 2.0 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTR causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. c.370C>T has been reported in the literature as p.Arg104Cys (legacy name) in an individual presenting with sensory axonal neuropathy, no neurological abnormalities in the upper limbs nor autonomic involvement. No evidence of amyloid deposition in muscle and nerve biopsies, no family history of amyloidosis. (example, Saraiva_1999) and more recently in one 80 year old female among a cohort of patients diagnosed to have cardiac amyloidosis (example, Maurizi_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy/Amyloidosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 30, 2016	- -

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

- -

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

- -

Hyperthyroxinemia, dystransthyretinemic;C2751492:Familial amyloid neuropathy;C5779776:Carpal tunnel syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 25, 2022

- -

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. -

Familial amyloid neuropathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

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	T
BayesDel_noAF	Uncertain	0.080
Cadd	Benign	22
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	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Uncertain	0.52	D;D;D;D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Benign	0.81	L;L;.;.
MutationTaster	Benign	0.99	N
PrimateAI	Benign	0.25	T
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	T
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

Other links and lift over

dbSNP: rs745834030; hg19: chr18-29178564; COSMIC: COSV52700989; COSMIC: COSV52700989;