rs121918069

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000371.4(TTR):c.233T>A(p.Leu78His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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. L78R) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

TTR
NM_000371.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 6.06

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a strand (size 3) in uniprot entity TTHY_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) 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 chr18-31595152-T-G is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.975

PP5

Variant 18-31595152-T-A is Pathogenic according to our data. Variant chr18-31595152-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-31595152-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTR	NM_000371.4 link	c.233T>A	p.Leu78His	missense_variant	Exon 3 of 4	ENST00000237014.8	NP_000362.1	P02766E9KL36

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TTR	ENST00000237014.8 link	c.233T>A	p.Leu78His	missense_variant	Exon 3 of 4	1	NM_000371.4	ENSP00000237014.4	P02766
TTR	ENST00000649620.1 link	c.233T>A	p.Leu78His	missense_variant	Exon 5 of 6			ENSP00000497927.1	P02766
TTR	ENST00000610404.5 link	c.137T>A	p.Leu46His	missense_variant	Exon 3 of 4	5		ENSP00000477599.2	A0A087WT59
TTR	ENST00000541025.2 link	n.259T>A		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000189

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Sep 09, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 06, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in association with amyloidosis and amyloidotic polyneuropathy; also reported as L58H due to alternative nomenclature (PMID: 20209591, 2613237, 26656838, 27724962, 34658264, 34461735, 33283548); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 1644839, 17503405, 19602727, 22620962, 25526974, 2613237, 27724962, 17143887, 1656975, 25604431, 26656838, 34461735, 34658264, 33283548, 37014422, 20209591, 15820680) -

Jul 25, 2016

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Amyloidosis, hereditary systemic 1

Pathogenic:4

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with histidine, which is basic and polar, at codon 78 of the TTR protein (p.Leu78His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (PMID: 2613237, 9196903, 17503405, 20209591, 25526974, 27724962). This variant is also known as p.Leu58His. ClinVar contains an entry for this variant (Variation ID: 13420). 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: 15820680, 19602727). For these reasons, this variant has been classified as Pathogenic. -

Nov 10, 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.233T>A (p.Leu78His) variant indicated to be located in the loop region (Cendron_2009) causes a missense change involving a conserved nucleotide with 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a damaging outcome for this variant. In addition, mutations in this residue (L78R) and in nearby residues (H76R, G77R, T79R, T79K) have been reported in association with amyloidosis, further supporting the functional importance of this region of the protein. The variant of interest was not observed in controls (ExAC, 1000 Gs, or ESP) and is a common TTR disease variant that is reported to be detected in >50 published cases, usually presenting with carpal tunnel syndrome and slowly progressing over two decades (Miller_2004). Multiple clinical diagnostic laboratories/databases cite the variant as "pathogenic." Therefore, the variant of interest has been classified as Pathogenic. -

Feb 27, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 31, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

_x000D_ Criteria applied: PS3, PM2_SUP, PM1_SUP, PM5, PS4_MOD -

Cardiovascular phenotype

Pathogenic:1

Feb 24, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L78H variant (also known as c.233T>A and L58H), located in coding exon 3 of the TTR gene, results from a T to A substitution at nucleotide position 233. The leucine at codon 78 is replaced by histidine, an amino acid with similar properties. This alteration has been seen in multiple individuals with familial transthyretin amyloidosis whose symptoms generally included carpal tunnel syndrome, generalized neuropathy, amyloid deposits and positive congo red staining (Nichols WC, et al. Genomics 1989;5(3):535-40; Barreiros AP, et al. Liver Transpl. 2010;16(3):314-23; Connors LH, et al. Biochim. Biophys. Acta 1998;1407(3):185-92; Ungerer MN et al. Amyloid, 2020 Dec;:1-9). In two additional studies, a small difference in the crystal structure of this variant compared with wild type was noted and the variant was shown to unfold 90% at 2.5M urea, indicating decreased conformation stability in the folded state (Altland K, et al. Electrophoresis 2007;28(12):2053-64; Cendron L, et al. J. Biol. Chem. 2009 Sep; 284(38):25832-41). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Zhang J et al. Environ Sci Technol, 2018 10;52:11865-11874). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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

Pathogenic

0.80

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.97

D;D;T;.

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.88

.;D;D;T

M_CAP

Pathogenic

0.69

MetaRNN

Pathogenic

0.98

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.2

H;H;.;.

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-6.2

.;D;.;.

REVEL

Pathogenic

0.98

Sift

Uncertain

0.0040

.;D;.;.

Sift4G

Uncertain

0.0040

.;D;D;D

Polyphen

1.0

D;D;.;.

Vest4

0.92, 0.91, 0.95

MVP

0.99

MPC

1.6

ClinPred

0.99

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.97

gMVP

0.98

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