rs121918093
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The NM_000371.4(TTR):c.118G>A(p.Val40Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,614,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
TTR
NM_000371.4 missense
NM_000371.4 missense
Scores
8
7
4
Clinical Significance
Conservation
PhyloP100: 7.59
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 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;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.871
PP5
Variant 18-31592944-G-A is Pathogenic according to our data. Variant chr18-31592944-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 13455.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-31592944-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152206Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461820Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727218
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152206Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74350
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Feb 24, 2021 | The TTR c.118G>A; p.Val40Ile variant (rs121918093), also known as p.Val20Ile, is reported in the literature in multiple individuals and one family affected with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (Auer-Grumbach 2020, Bauer 2014, Jenne 1996). Functional analyses of the variant protein show significantly reduced tetramer stability (Jenne 1996, Atland 2007, Sekijima 2005). This variant is also reported in ClinVar (Variation ID: 13455). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The valine at codon 40 is highly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.697). 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. Auer-Grumbach M et al. Hereditary ATTR Amyloidosis in Austria: Prevalence and Epidemiological Hot Spots. J Clin Med. 2020 Jul 14;9(7):2234. Bauer R et al. The "Wagshurst study": p.Val40Ile transthyretin gene variant causes late-onset cardiomyopathy. Amyloid. 2014 Dec;21(4):267-75. Jenne DE et al. A new isoleucine substitution of Val-20 in transthyretin tetramers selectively impairs dimer-dimer contacts and causes systemic amyloidosis. Proc Natl Acad Sci U S A. 1996 Jun 25;93(13):6302-7. Sekijima Y et al. The biological and chemical basis for tissue-selective amyloid disease. Cell. 2005 Apr 8;121(1):73-85. - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 24, 2017 | This variant is denoted p.Val40Ile (V40I) GTC>ATC: c.118 G>A in exon 2 of the TTR gene (NM_000371.3). The Val40Ile variant (also known as Val20Ile, due to a difference in cDNA numbering) in the TTR gene, has been published in association with cardiac amyloidosis (Jenne D et al., 1996; Barreiros A et al., 2010). Jenne et al. (1996) reported the Val40Ile mutation in a German family with severe amyloid cardiomyopathy. The same study demonstrated that Val40Ile causes significant loss of tetramer stability. Barreiros et al. (2010) reported Val40Ile in a 56 year old patient with sensory-motor polyneuropathy and restrictive cardiomyopathy. Mutations in nearby codons (Asp38Asn, Asp38Gly, Asp38Glu, Ser43Asn) have also been reported in association with amyloidosis, further supporting the functional importance of this region of the protein. Furthermore, Val40Ile was not detected in up to 400 control alleles from Caucasian and African American individuals tested at GeneDx, indicating it is not a common benign polymorphism in these populations. The variant is found in TTR panel(s). - |
Amyloidosis, hereditary systemic 1 Pathogenic:3
Pathogenic, no assertion criteria provided | clinical testing | Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals | Feb 21, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 18, 2024 | This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 40 of the TTR protein (p.Val40Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (PMID: 20209591, 25291558). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Val20Ile. ClinVar contains an entry for this variant (Variation ID: 13455). 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: 8692810, 15820680, 17503405). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 13, 1997 | - - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 19, 2024 | The c.118G>A (p.V40I) alteration is located in exon 2 (coding exon 2) of the TTR gene. This alteration results from a G to A substitution at nucleotide position 118, causing the valine (V) at amino acid position 40 to be replaced by an isoleucine (I). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This pathogenic variant (also referred to as V20I) was first described in a 60-year-old German patient with amyloid cardiomyopathy and in 4 asymptomatic, but young, family members; the TTR protein in the plasma of the carriers of this alteration was found to be unstable (Jenne, 1996). This pathogenic variant was also identified in a 50-year-old man and his mother, both of whom had cardiac amyloidosis; the authors suggest that this alteration may be associated with a late-onset form of cardiac amyloidosis (Jacobson, 1997). Another study in a cohort of 59 related individuals from a small village in southern Germany, in which this variant was prevalent, concluded that this variant results in a predominantly cardiac phenotype with high penetrance and late onset of symptoms (Bauer, 2014). In a retrospective study of 4459 patients in the United Kingdom who underwent TTR sequencing following referral for known or suspected amyloidosis, this alteration was detected in 7 individuals (0.16%) (Rowczenio, 2019). This amino acid position is highly conserved in available vertebrate species. A functional study found that, although the monomer of the protein with this alteration was more stable than the wild type, the dimer-dimer interaction appeared to be weakened, possibly leading to instability of the protein and a potential mechanism for reduced TTR concentration in plasma that was observed in carriers of the alteration (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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;D;T;.
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H;.;.
PrimateAI
Benign
T
PROVEAN
Benign
.;N;.;.
REVEL
Pathogenic
Sift
Uncertain
.;D;.;.
Sift4G
Uncertain
.;D;D;D
Polyphen
D;D;.;.
Vest4
0.55, 0.54, 0.46
MutPred
Gain of methylation at K35 (P = 0.0905);Gain of methylation at K35 (P = 0.0905);Gain of methylation at K35 (P = 0.0905);Gain of methylation at K35 (P = 0.0905);
MVP
0.99
MPC
1.2
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at