rs121918093

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_000371.4(TTR):c.118G>A(p.Val40Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,614,026 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. V40A) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TTR
NM_000371.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 7.59

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 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 chr18-31592945-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2169600.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.871

PP5

Variant 18-31592944-G-A is Pathogenic according to our data. Variant chr18-31592944-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 13455.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-31592944-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTR	NM_000371.4 linkuse as main transcript	c.118G>A	p.Val40Ile	missense_variant	2/4	ENST00000237014.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTR	ENST00000237014.8 linkuse as main transcript	c.118G>A	p.Val40Ile	missense_variant	2/4	1	NM_000371.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

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

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461820

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 24, 2021	The TTR c.118G>A; p.Val40Ile variant (rs121918093), also known as p.Val20Ile, is reported in the literature in multiple individuals and one family affected with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (Auer-Grumbach 2020, Bauer 2014, Jenne 1996). Functional analyses of the variant protein show significantly reduced tetramer stability (Jenne 1996, Atland 2007, Sekijima 2005). This variant is also reported in ClinVar (Variation ID: 13455). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The valine at codon 40 is highly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.697). Based on available information, this variant is considered to be pathogenic. References: Altland K et al. Genetic microheterogeneity of human transthyretin detected by IEF. Electrophoresis. 2007 Jun;28(12):2053-64. Auer-Grumbach M et al. Hereditary ATTR Amyloidosis in Austria: Prevalence and Epidemiological Hot Spots. J Clin Med. 2020 Jul 14;9(7):2234. Bauer R et al. The "Wagshurst study": p.Val40Ile transthyretin gene variant causes late-onset cardiomyopathy. Amyloid. 2014 Dec;21(4):267-75. Jenne DE et al. A new isoleucine substitution of Val-20 in transthyretin tetramers selectively impairs dimer-dimer contacts and causes systemic amyloidosis. Proc Natl Acad Sci U S A. 1996 Jun 25;93(13):6302-7. Sekijima Y et al. The biological and chemical basis for tissue-selective amyloid disease. Cell. 2005 Apr 8;121(1):73-85. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 24, 2017	This variant is denoted p.Val40Ile (V40I) GTC>ATC: c.118 G>A in exon 2 of the TTR gene (NM_000371.3). The Val40Ile variant (also known as Val20Ile, due to a difference in cDNA numbering) in the TTR gene, has been published in association with cardiac amyloidosis (Jenne D et al., 1996; Barreiros A et al., 2010). Jenne et al. (1996) reported the Val40Ile mutation in a German family with severe amyloid cardiomyopathy. The same study demonstrated that Val40Ile causes significant loss of tetramer stability. Barreiros et al. (2010) reported Val40Ile in a 56 year old patient with sensory-motor polyneuropathy and restrictive cardiomyopathy. Mutations in nearby codons (Asp38Asn, Asp38Gly, Asp38Glu, Ser43Asn) have also been reported in association with amyloidosis, further supporting the functional importance of this region of the protein. Furthermore, Val40Ile was not detected in up to 400 control alleles from Caucasian and African American individuals tested at GeneDx, indicating it is not a common benign polymorphism in these populations. The variant is found in TTR panel(s). -

Familial amyloid neuropathy

Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	Feb 21, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 10, 2023	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 40 of the TTR protein (p.Val40Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (PMID: 20209591, 25291558). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Val20Ile. ClinVar contains an entry for this variant (Variation ID: 13455). 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. Experimental studies have shown that this missense change affects TTR function (PMID: 8692810, 15820680, 17503405). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 13, 1997	- -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 19, 2024

The c.118G>A (p.V40I) alteration is located in exon 2 (coding exon 2) of the TTR gene. This alteration results from a G to A substitution at nucleotide position 118, causing the valine (V) at amino acid position 40 to be replaced by an isoleucine (I). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This pathogenic variant (also referred to as V20I) was first described in a 60-year-old German patient with amyloid cardiomyopathy and in 4 asymptomatic, but young, family members; the TTR protein in the plasma of the carriers of this alteration was found to be unstable (Jenne, 1996). This pathogenic variant was also identified in a 50-year-old man and his mother, both of whom had cardiac amyloidosis; the authors suggest that this alteration may be associated with a late-onset form of cardiac amyloidosis (Jacobson, 1997). Another study in a cohort of 59 related individuals from a small village in southern Germany, in which this variant was prevalent, concluded that this variant results in a predominantly cardiac phenotype with high penetrance and late onset of symptoms (Bauer, 2014). In a retrospective study of 4459 patients in the United Kingdom who underwent TTR sequencing following referral for known or suspected amyloidosis, this alteration was detected in 7 individuals (0.16%) (Rowczenio, 2019). This amino acid position is highly conserved in available vertebrate species. A functional study found that, although the monomer of the protein with this alteration was more stable than the wild type, the dimer-dimer interaction appeared to be weakened, possibly leading to instability of the protein and a potential mechanism for reduced TTR concentration in plasma that was observed in carriers of the alteration (Altland, 2007). 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

Benign

0.13

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.33

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.76

D;D;T;.

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.93

M_CAP

Pathogenic

0.47

MetaRNN

Pathogenic

0.87

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.6

H;H;.;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.42

Polyphen

1.0

D;D;.;.

Vest4

0.55, 0.54, 0.46

MutPred

0.64

Gain of methylation at K35 (P = 0.0905);Gain of methylation at K35 (P = 0.0905);Gain of methylation at K35 (P = 0.0905);Gain of methylation at K35 (P = 0.0905);

MVP

0.99

MPC

1.2

ClinPred

0.99

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.79

gMVP

0.92

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