18-31591916-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PP2BP4_StrongBP6BS2_Supporting

The NM_000371.4(TTR):c.14G>A(p.Arg5His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000141 in 1,614,140 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R5C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00018 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

TTR
NM_000371.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10B:9O:1

Conservation

PhyloP100: -0.437

Publications

11 publications found

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 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

TTR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.03921768).

BP6

Variant 18-31591916-G-A is Benign according to our data. Variant chr18-31591916-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 181697.

BS2

High AC in GnomAd4 at 27 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 rank	MANE	Protein	UniProt
TTR	NM_000371.4 link	c.14G>A	p.Arg5His	missense_variant	Exon 1 of 4	ENST00000237014.8	NP_000362.1	P02766E9KL36

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTR	ENST00000237014.8 link	c.14G>A	p.Arg5His	missense_variant	Exon 1 of 4	1	NM_000371.4	ENSP00000237014.4		P02766

Frequencies

GnomAD3 genomes

AF:

0.000177

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000660

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000111

AC:

AN:

251406

AF XY:

0.000103

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.000277

Gnomad NFE exome

AF:

0.000150

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000137

AC:

200

AN:

1461862

Hom.:

Cov.:

AF XY:

0.000128

AC XY:

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.0000894

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000927

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.000356

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000143

AC:

159

AN:

1112002

Other (OTH)

AF:

0.000149

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000177

AC:

AN:

152278

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41558

American (AMR)

AF:

0.000131

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.000660

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000250

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000267

Hom.:

Bravo

AF:

0.0000945

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000107

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10Benign:9Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4Benign:6

Apr 26, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 21, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported in an individual with HCM who also harbored a variant in the MYBPC3 gene in published literature (Viswanathan et al., 2017); however, no segregation studies were described; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27249223, 31659433, 29121657, 32674397) -

Mar 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 14, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The TTR c.14G>A; p.Arg5His variant (rs138657343) is reported in the literature in an individual affected with hereditary transthyretin amyloidosis (Auer-Grumbach 2020) as well as in an individual with hypertrophic cardiomyopathy (Viswanathan 2017). This variant is also reported in ClinVar (Variation ID: 181697). It is found in the general population with an overall allele frequency of 0.013% (36/282806 alleles, including 1 homozygote) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.268). However, given the lack of clinical and functional data, the significance of the p.Arg5His variant is uncertain at this time. References: Auer-Grumbach M et al. Hereditary ATTR Amyloidosis in Austria: Prevalence and Epidemiological Hot Spots. J Clin Med. 2020 Jul 14;9(7):2234. PMID: 32674397. Viswanathan SK et al. Hypertrophic cardiomyopathy clinical phenotype is independent of gene mutation and mutation dosage. PLoS One. 2017 Nov 9;12(11):e0187948. PMID: 29121657. -

Oct 09, 2019

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Amyloidosis, hereditary systemic 1

Uncertain:3Other:1

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant classified as Uncertain significance and reported on 11-03-2021 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Dec 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 5 of the TTR protein (p.Arg5His). This variant is present in population databases (rs138657343, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of TTR-related conditions (PMID: 29121657, 32674397). ClinVar contains an entry for this variant (Variation ID: 181697). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Aug 29, 2019

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Cardiomyopathy

Uncertain:1

Mar 21, 2023

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

TTR-related disorder

Uncertain:1

Jun 01, 2023

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The TTR c.14G>A variant is predicted to result in the amino acid substitution p.Arg5His. This variant was reported in an individual with Cardiomyopathy, hypertrophic (Table S3 Viswanathan et al. 2017. PubMed ID: 29121657) and in an individual with hereditary amyloidosis (Auer-Grumbach et al. 2020. PubMed ID: 32674397). This variant is reported in 0.032% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/18-29171879-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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

Uncertain:1

Mar 04, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Charcot-Marie-Tooth disease

Benign:1

Molecular Genetics Laboratory, London Health Sciences Centre

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Aug 23, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Arg5His in exon 1 of TTR: This variant is not expected to have clinical signif icance due to a lack of conservation across species, including mammals. Of note, >15 mammals, including chimpanzee, have a histidine (His) at this position. Thi s variant has been identified in 21/126636 European chromosomes, including 1 hom ozygote, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitut e.org; dbSNP rs138657343). -

Cardiovascular phenotype

Benign:1

Apr 19, 2023

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.26

CADD

Benign

2.9

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.20

T;T;T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.051

LIST_S2

Benign

0.61

.;T;T;T

M_CAP

Benign

0.022

MetaRNN

Benign

0.039

T;T;T;T

MetaSVM

Uncertain

-0.23

MutationAssessor

Benign

0.48

N;N;.;.

PhyloP100

-0.44

PrimateAI

Benign

0.20

PROVEAN

Benign

-0.55

.;N;.;.

REVEL

Benign

0.27

Sift

Benign

0.19

.;T;.;.

Sift4G

Benign

0.18

.;T;T;T

Polyphen

0.0020

B;B;.;.

Vest4

0.024, 0.086, 0.074

MVP

0.82

MPC

0.58

ClinPred

0.017

GERP RS

-5.1

PromoterAI

-0.21

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.031

gMVP

0.64

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over