rs121918085

Positions:

chr18-31595181-A-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PS1PM1PP3PP5_Very_Strong

The NM_000371.4(TTR):c.262A>T(p.Ile88Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,613,992 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I88T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

TTR
NM_000371.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: -2.06

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 15 ACMG points.

PS1

Transcript NM_000371.4 (TTR) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd

PM1

In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000371.4

PP3

MetaRNN computational evidence supports a deleterious effect, 0.747

PP5

Variant 18-31595181-A-T is Pathogenic according to our data. Variant chr18-31595181-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13446.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-31595181-A-T 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.262A>T	p.Ile88Leu	missense_variant	3/4	ENST00000237014.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
TTR	ENST00000237014.8 linkuse as main transcript	c.262A>T	p.Ile88Leu	missense_variant	3/4	1	NM_000371.4	P1
TTR	ENST00000649620.1 linkuse as main transcript	c.262A>T	p.Ile88Leu	missense_variant	5/6			P1
TTR	ENST00000610404.5 linkuse as main transcript	c.166A>T	p.Ile56Leu	missense_variant	3/4	5
TTR	ENST00000541025.2 linkuse as main transcript	n.288A>T		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251440

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135886

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1461828

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.0000135

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.0000724

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000264

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 09, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies showed that although mutant protein could be distinguished from wild type protein, it showed no change in conformational stability compared to wild type (Altland et al., 2007); This variant is associated with the following publications: (PMID: 31371117, 1786038, 8038017, 14640031, 21540676, 22745357, 23713495, 26428663, 26537620, 28635949, 30638075, 31589614, 36444226, 17503405, 24767411, 18544157, 34746851, 30070416, 24184229, 34622675, 30683924, 33844361, 28188196, 34658264, 34828392, 34047656, 35717381, 28494620) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 07, 2020	The frequency of this variant in the general population is consistent with pathogenicity. This variant is statistically more frequent in affected individuals than in the general population. Statistically associated with disease in multiple families. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 17, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 19, 2023	PP4, PM2, PS4 -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 14, 2021	The TTR c.262A>T; p.Ile88Leu variant (rs121918085), also known as p.Ile88Leu, is reported in the literature in multiple individuals affected with hereditary transthyretin amyloidosis (Damy 2016, Ihse 2013, Iorio 2017, Mauzrizi 2020) and segregated with disease in at least one family (Rapezzi 2013). This variant is also reported in ClinVar (Variation ID: 13446). This variant is found in the non-Finnish European population with an allele frequency of 0.0018% (5/129164 alleles) in the Genome Aggregation Database. The isoleucine at codon 88 is weakly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.554). Based on available information, this variant is considered to be likely pathogenic. References: 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. Ihse E et al. Amyloid fibrils containing fragmented ATTR may be the standard fibril composition in ATTR amyloidosis. Amyloid. 2013 Sep;20(3):142-50. PMID: 23713495. Iorio A et al. Non-coding variants contribute to the clinical heterogeneity of TTR amyloidosis. Eur J Hum Genet. 2017 Sep;25(9):1055-1060. PMID: 28635949. Maurizi N et al. Prevalence of cardiac amyloidosis among adult patients referred to tertiary centres with an initial diagnosis of hypertrophic cardiomyopathy. Int J Cardiol. 2020 Feb 1;300:191-195. PMID: 31371117. Rapezzi C et al. Disease profile and differential diagnosis of hereditary transthyretin-related amyloidosis with exclusively cardiac phenotype: an Italian perspective. Eur Heart J. 2013 Feb;34(7):520-8. PMID: 22745357. -

Amyloidosis, hereditary systemic 1

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 17, 2023	This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 88 of the TTR protein (p.Ile88Leu). This variant is present in population databases (rs121918085, gnomAD 0.004%). This missense change has been observed in individual(s) with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (PMID: 1786038, 22745357, 26428663, 26537620). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13446). 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 95%. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	May 11, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 27, 2020	The p.Ile88Leu variant in TTR (also described as p.Ile68Leu in the literature) has been identified in >20 individuals with clinical features of hereditary transthyretin amyloidosis (ATTR; Almeida 1991 PMID: 1786038, Hesse 1993 PMID: 8038017, Salvi 2003 PMID: 14640031, Perfetto 2011 PMID: 21540676, Ihse 2013 PMID: 23713495, Rapezzi 2013 PMID: 22745357, Cappelli 2016 PMID: 26428663, Damy 2016 PMID: 26537620, Iorio 2017 PMID: 28635949, Maurizi 2020 PMID: 31371117) and segregated with disease in at least 5 individuals from at least one family (Rapezzi 2013 PMID: 22745357). Clinical features in affected individuals included a mostly cardiac amyloidosis phenotype, with some neurologic and mixed cardiac/neurologic phenotypes. This variant has also been reported by another clinical laboratory in ClinVar (Variation ID 13446) and has been identified in 0.004% (5/129164) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Results from an in vitro functional study using electrophoretic analyses to assess the role of this variant show that while variant p.Ile88Leu TTR monomer could be clearly distinguished from its wild type counterpart, it did not result in a reduced conformational stability of both TTR monomers and tetramers (Altland 2007 PMID: 17503405). Therefore, the clinical significance of these results is uncertain. Additionally, 7 mammals (squirrel, antelope, cow, goat, sheep, Tasmanian devil, opossum) carry a Leucine (Leu) at this position with moderate nearby amino acid conservation and additional computational tools suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant ATTR based upon presence in multiple affected individuals and segregation studies. ACMG/AMP criteria applied: PS4, PM2, PP1_Moderate, BP4. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 1993	- -

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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 24, 2022

- -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 14, 2023

The p.I88L pathogenic mutation (also known as c.262A>T and I68L), located in coding exon 3 of the TTR gene, results from an A to T substitution at nucleotide position 262. The isoleucine at codon 88 is replaced by leucine, an amino acid with highly similar properties. This pathogenic mutation was first described in a German male with cardiac amyloidosis and dysaesthesia in both hands (Almeida MR et al. Basic Res Cardiol. 1991; 86(6):567-71). A large multicenter study in the Italian population found this pathogenic mutation to be the third most common TTR mutation, and the most common TTR mutation with a predominantly cardiac phenotype; it was identified in 27 individuals from 22 families, 23 of whom had a predominantly cardiac phenotype, 3 of whom had a predominantly neurologic phenotype, and 1 of whom had a mixed phenotype (Rapezzi C et al. Eur Heart J. 2013; 34(7):520-8). One functional study showed this mutation has minimal effect to the stability of the protein structure; however, this analysis does not capture how mutations in TTR result in pathology (Atland K et al. Electrophoresis 2007 Jun;28(12):2053-64). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Uncertain

0.067

BayesDel_noAF

Uncertain

0.040

CADD

Benign

0.089

DANN

Benign

0.75

DEOGEN2

Uncertain

0.68

D;D;T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.022

LIST_S2

Benign

0.75

.;T;T;T

M_CAP

Benign

0.084

MetaRNN

Pathogenic

0.75

D;D;D;D

MetaSVM

Benign

-0.54

MutationAssessor

Benign

0.33

N;N;.;.

MutationTaster

Benign

9.2e-9

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.75

.;N;.;.

REVEL

Uncertain

0.55

Sift

Benign

0.30

.;T;.;.

Sift4G

Benign

0.52

.;T;T;T

Polyphen

0.0

B;B;.;.

Vest4

0.29, 0.40, 0.65

MutPred

0.52

Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);

MVP

0.98

MPC

0.46

ClinPred

0.043

GERP RS

-8.9

Varity_R

0.48

gMVP

0.87

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