rs121918089

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PM5PP5_Very_Strong

The NM_000371.4(TTR):c.379A>G(p.Ile127Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I127M) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

TTR
NM_000371.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 4.01

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 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

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

PP5

Variant 18-31598610-A-G is Pathogenic according to our data. Variant chr18-31598610-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-31598610-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTR	NM_000371.4 link	c.379A>G	p.Ile127Val	missense_variant	Exon 4 of 4	ENST00000237014.8	NP_000362.1	P02766E9KL36
LOC124904277	XR_007066326.1 link	n.129-2915T>C		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TTR	ENST00000237014.8 link	c.379A>G	p.Ile127Val	missense_variant	Exon 4 of 4	1	NM_000371.4	ENSP00000237014.4	P02766
TTR	ENST00000649620.1 link	c.379A>G	p.Ile127Val	missense_variant	Exon 6 of 6			ENSP00000497927.1	P02766
TTR	ENST00000610404.5 link	c.283A>G	p.Ile95Val	missense_variant	Exon 4 of 4	5		ENSP00000477599.2	A0A087WT59

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6

Oct 26, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate that TTR dimers from individuals heterozygous for TTRI127V are less stable than dimers from wild type individuals (Atland K et al., 2007); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as I107V; This variant is associated with the following publications: (PMID: 22301727, 8081397, 30306720, 20209591, 22745357, 19781421, 12039669, 7914929, 24101130, 32723050, 33481097, 33188503, 33844361, 34668655, 34602081, 34746851, 33283548, 34391735, 35665045, 35599006, 35417510, 35346209, 35331287, ScirpaR2022, 17443043, 9748014, 27025994, 27066555, 34658264, 26537620, 29520877, 26656838, 34440326, 35637921, 35580748, 17503405) -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 27, 2024

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. In some published literature, this variant is referred to as p.Ile107Val. -

Jul 26, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TTR: PM2, PM5, PS3:Moderate, PS4:Supporting -

Mar 21, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TTR c.379A>G, p.Ile127Val variant (rs121918089, ClinVar ID: 13450), also known as Ile107Val, is reported in several individuals with amyloidosis and polyneuropathy (Damy 2016, Dohrn 2013, Barreiros 2010, Jacobsen 1994, Pozsonyi 2021, Skrahina 2021, Suhr 2016, Uemich 1994). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Functional characterization of the variant protein indicates a slight decrease in monomer stability, but significant decreases in the stability of TTR dimers and tetramers (Altland 2007). Additionally, other amino acid substitutions at this codon (c.381T>G, p.Ile127Met; c.379A>T, p.Ile127Phe) have been reported to be associated with amyloidosis and polyneuropathy (Benson 2007, Connors 2003). 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. PMID: 17503405. Barreiros AP et al. Liver transplantation and combined liver-heart transplantation in patients with familial amyloid polyneuropathy: a single-center experience. Liver Transpl. 2010 Mar;16(3):314-23. PMID: 20209591. Benson MD et al. The molecular biology and clinical features of amyloid neuropathy. Muscle Nerve. 2007 Oct;36(4):411-23. PMID: 17554795. Connors LH et al. Tabulation of human transthyretin (TTR) variants, 2003. Amyloid. 2003 Sep;10(3):160-84. PMID: 14640030. Jacobson DR et al. Transthyretin VAL107, a new variant associated with familial cardiac and neuropathic amyloidosis. Hum Mutat. 1994;3(4):399-401. PMID: 8081397. Damy T et al. Prevalence and clinical phenotype of hereditary transthyretin amyloid cardiomyopathy in patients with increased left ventricular wall thickness. Eur Heart J. 2016 Jun 14;37(23):1826-34. PMID: 26537620. Dohrn MF et al. Diagnostic hallmarks and pitfalls in late-onset progressive transthyretin-related amyloid-neuropathy. J Neurol. 2013 Dec;260(12):3093-108. PMID: 24101130. Pozsonyi Z et al. Variant Transthyretin Amyloidosis (ATTRv) in Hungary: First Data on Epidemiology and Clinical Features. Genes (Basel). 2021 Jul 28;12(8):1152. PMID: 34440326. Skrahina V et al. Hereditary transthyretin-related amyloidosis is frequent in polyneuropathy and cardiomyopathy of no obvious aetiology. Ann Med. 2021 Dec;53(1):1787-1796. PMID: 34658264. Suhr OB et al. Survival After Transplantation in Patients With Mutations Other Than Val30Met: Extracts From the FAP World Transplant Registry. Transplantation. 2016 Feb;100(2):373-81. PMID: 26656838. Uemichi T et al. Amyloid polyneuropathy in two German-American families: a new transthyretin variant (Val 107). J Med Genet. 1994 May;31(5):416-7. PMID: 7914929. -

Amyloidosis, hereditary systemic 1

Pathogenic:4

May 01, 1994

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 26, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The TTR c.379A>G variant affects a conserved nucleotide, resulting in amino acid change from Ile to Val. 3/4 in-silico tools predict this variant to be benign (SNPs&GO not captured due to low reliability index). However, functional studies indicate that TTRI107V dimers and tetramers decreased stability compared to controls. This variant is not found in 121416 control chromosomes, but has been cited in numerous ATTR patients from various ethnicities. Taken together, this is a disease variant and was classified as pathogenic. -

May 28, 2019

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 127 of the TTR protein (p.Ile127Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with amyloidosis (PMID: 7914929, 8081397, 9748014, 20209591, 24101130, 26537620, 27025994, 27066555). This variant is also known as p.Ile107Val. ClinVar contains an entry for this variant (Variation ID: 13450). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt TTR protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects TTR function (PMID: 17503405). This variant disrupts the p.Ile127 amino acid residue in TTR. Other variant(s) that disrupt this residue have been observed in individuals with TTR-related conditions (PMID: 22745357, 24480837), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

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

Pathogenic:1

Jan 13, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary amyloidosis

Pathogenic:1

Feb 22, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS3 strong, PS4 strong, PM2 moderated -

Cardiovascular phenotype

Pathogenic:1

Dec 08, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.379A>G (p.I127V) alteration is located in exon 4 (coding exon 4) of the TTR gene. This alteration results from a A to G substitution at nucleotide position 379, causing the isoleucine (I) at amino acid position 127 to be replaced by a valine (V). Based on data from the Genome Aggregation Database (gnomAD), the TTR c.379A>G alteration was not observed with coverage at this location. This variant, historically known as p.I107V, has been detected in multiple individuals with TTR-related amyloidosis (Jacobson, 1994; Planté-Bordeneuve, 1998; Damy, 2016; Kuzume, 2016). Two different alterations located at the same amino acid position, p.I127F (c.379A>T, historically known as p.I107F) and p.I127M (c.381T>G, historically known as p.I107M), have also been detected in individuals with TTR-related amyloidosis (Cappellari, 2011; Lv, 2014). This amino acid is highly conserved in available vertebrate species. Functional studies indicate that this variant results in unstable interaction between transthyretin tetramers (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

0.27

BayesDel_noAF

Pathogenic

0.15

CADD

Benign

DANN

Benign

0.47

DEOGEN2

Uncertain

0.61

D;D;.

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.35

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.79

.;T;T

M_CAP

Uncertain

0.087

MetaRNN

Uncertain

0.50

D;D;D

MetaSVM

Uncertain

0.14

MutationAssessor

Benign

1.1

L;L;.

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.26

.;N;.

REVEL

Uncertain

0.53

Sift

Benign

0.40

.;T;.

Sift4G

Benign

0.51

.;T;T

Polyphen

0.013

B;B;.

Vest4

0.40, 0.74

MutPred

0.64

Gain of glycosylation at S132 (P = 0.0885);Gain of glycosylation at S132 (P = 0.0885);.;

MVP

0.94

MPC

0.40

ClinPred

0.50

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.61

gMVP

0.88

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