rs121918073
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate
The NM_000371.4(TTR):c.391C>A(p.Leu131Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 (★). Synonymous variant affecting the same amino acid position (i.e. L131L) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 33)
Consequence
TTR
NM_000371.4 missense
NM_000371.4 missense
Scores
9
3
2
Clinical Significance
Conservation
PhyloP100: 2.61
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM1
?
In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 7 uncertain in NM_000371.4
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.974
PP5
?
Variant 18-31598622-C-A is Pathogenic according to our data. Variant chr18-31598622-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13424.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr18-31598622-C-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TTR | NM_000371.4 | c.391C>A | p.Leu131Met | missense_variant | 4/4 | ENST00000237014.8 | |
LOC124904277 | XR_007066326.1 | n.129-2927G>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTR | ENST00000237014.8 | c.391C>A | p.Leu131Met | missense_variant | 4/4 | 1 | NM_000371.4 | P1 | |
TTR | ENST00000649620.1 | c.391C>A | p.Leu131Met | missense_variant | 6/6 | P1 | |||
TTR | ENST00000610404.5 | c.295C>A | p.Leu99Met | missense_variant | 4/4 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 30, 2023 | The p.L131M variant (also known as c.391C>A), located in coding exon 4 of the TTR gene, results from a C to A substitution at nucleotide position 391. The leucine at codon 131 is replaced by methionine, an amino acid with highly similar properties. This alteration, which is also reported as p.L111M, has been detected in several individuals with transthyretin (TTR) amyloidosis and related cardiomyopathy and TTR amyloidosis cohorts (Nordlie M et al. Scand J Immunol, 1988 Jan;27:119-22; Altland K et al. Electrophoresis, 2007 Jun;28:2053-64; Nelson LM et al. Clin Transplant, 2013 Dec;27:203-9; Suhr OB et al. Transplantation, 2016 Feb;100:373-81; Damy T et al. Eur Heart J, 2019 Apr;43:391-400; Caponetti AG et al. JACC Heart Fail, 2021 Oct;9:736-746; Barroso FA et al. Amyloid, 2022 Sep;29:175-183; Dispenzieri A et al. Orphanet J Rare Dis, 2022 Jun;17:236). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 majority of available evidence to date, this variant is likely to be pathogenic. - |
Familial amyloid neuropathy Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 1993 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H;.
MutationTaster
Benign
A
PrimateAI
Uncertain
T
Polyphen
D;D;.
Vest4
0.66, 0.83
MutPred
Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);.;
MVP
0.99
MPC
1.3
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at