rs121918094
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000371.4(TTR):c.95T>C(p.Leu32Pro) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L32V) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 32)
Consequence
TTR
NM_000371.4 missense
NM_000371.4 missense
Scores
11
2
1
Clinical Significance
Conservation
PhyloP100: 6.11
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 18 ACMG points.
PM1
?
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 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 chr18-31592920-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 1075407.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.991
PP5
?
Variant 18-31592921-T-C is Pathogenic according to our data. Variant chr18-31592921-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 13457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-31592921-T-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TTR | NM_000371.4 | c.95T>C | p.Leu32Pro | missense_variant | 2/4 | ENST00000237014.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTR | ENST00000237014.8 | c.95T>C | p.Leu32Pro | missense_variant | 2/4 | 1 | NM_000371.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial amyloid neuropathy Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 1999 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 23, 2023 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TTR function (PMID: 15820680). 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. ClinVar contains an entry for this variant (Variation ID: 13457). This variant is also known as Leu12Pro. This missense change has been observed in individual(s) with TTR-related conditions (PMID: 10071047, 20209591). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 32 of the TTR protein (p.Leu32Pro). - |
not specified Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jun 05, 2019 | The TTR c.95T>C; p.Leu32Pro variant (rs121918094), also known as p.Leu12Pro in alternative nomenclature, is reported in the literature in multiple individuals affected with TTR amyloidosis, including several individuals presenting with leptomeningeal amyloidosis (Brett 1999, McColgan 2015) and two siblings presenting with seizures and hypertrophic heart disease (Barreiros 2010). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The leucine at codon 32 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Consistent with these predictions, functional studies indicate that variant protein forms aggregates in cultured cells and mouse hepatocytes (Batista 2013) and exhibits altered multimerization properties compared to wildtype protein (Altland 2007). 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. 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. Batista AR et al. Hepatic production of transthyretin L12P leads to intracellular lysosomal aggregates in a new somatic transgenic mouse model. Biochim Biophys Acta. 2013 Aug;1832(8):1183-93. Brett M et al. Transthyretin Leu12Pro is associated with systemic, neuropathic and leptomeningeal amyloidosis. Brain. 1999 Feb;122 ( Pt 2):183-90. McColgan P et al. Oculoleptomeningeal Amyloidosis associated with transthyretin Leu12Pro in an African patient. J Neurol. 2015 Jan;262(1):228-34. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;D;T;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H;.;.
MutationTaster
Benign
A
PrimateAI
Uncertain
T
Polyphen
D;D;.;.
Vest4
0.96, 0.96, 0.93
MutPred
Gain of disorder (P = 0.018);Gain of disorder (P = 0.018);Gain of disorder (P = 0.018);Gain of disorder (P = 0.018);
MVP
0.99
MPC
1.7
ClinPred
D
GERP RS
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