rs121918071
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PM5PP3PP5_Very_Strong
The NM_000371.4(TTR):c.290C>A(p.Ser97Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,872 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S97F) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
TTR
NM_000371.4 missense
NM_000371.4 missense
Scores
7
9
3
Clinical Significance
Conservation
PhyloP100: 5.98
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 15 ACMG points.
PM1
In a helix (size 6) in uniprot entity TTHY_HUMAN there are 5 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 chr18-31595209-C-T is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.834
PP5
Variant 18-31595209-C-A is Pathogenic according to our data. Variant chr18-31595209-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-31595209-C-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| TTR | ENST00000237014.8 | c.290C>A | p.Ser97Tyr | missense_variant | 3/4 | 1 | NM_000371.4 | ENSP00000237014.4 | ||
| TTR | ENST00000649620.1 | c.290C>A | p.Ser97Tyr | missense_variant | 5/6 | ENSP00000497927.1 | ||||
| TTR | ENST00000610404.5 | c.194C>A | p.Ser65Tyr | missense_variant | 3/4 | 5 | ENSP00000477599.2 | |||
| TTR | ENST00000541025.2 | n.316C>A | non_coding_transcript_exon_variant | 3/3 | 2 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461872Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727236
GnomAD4 exome
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3
AN:
1461872
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Cov.:
31
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AC XY:
2
AN XY:
727236
Gnomad4 AFR exome
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GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Amyloidosis, hereditary systemic 1 Pathogenic:3
| Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 1998 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 05, 2024 | This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 97 of the TTR protein (p.Ser97Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hereditary amyloidosis (PMID: 1981182, 2891727, 9748014, 9771673, 25997029, 26017327). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Ser77Tyr. ClinVar contains an entry for this variant (Variation ID: 13422). 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 80%. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 15, 2016 | Variant summary: The TTR c.290C>A variant affects a conserved nucleotide, resulting in amino acid change from Ser to Tyr. 3/4 in-silico tools predict this variant to be damaging (SNPs&GO not captured due to low reliability index). Functional studies have shown Ser97Tyr (a.k.a. Tyr77) to have reduced conformational stability of monomers and tetramers. This variant was not found in 121366 control chromosomes. After the met30 mutation (176300.0001), the tyr77 mutation is the most prevalent in ATTR patients (OMIM). In addition, multiple reputable databases list this variant in assoication with hereditary amyloidosis. Taken together, this variant was classified as pathogenic. - |
not provided Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Sep 19, 2023 | This variant has been identified in multiple unrelated individuals with clinical features of transthyretin-related amyloidosis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In some published literature, this variant is referred to as Ser77Tyr. Assessment of experimental evidence suggests this variant results in abnormal protein function. Experiments indicate this variant results in reduced tetramer stability compared to wild-type (PMID: 17503405). - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 09, 2018 | The S97Y pathogenic variant in the TTR gene (also reported as S77Y due to alternative nomenclature) has been published multiple times in association with polyneuropathy and amyloidosis (Wallace et al., 1988; Swiecicki et al. 2015; Fontana et al., 1988; Carr et al., 2016); however, no familial segregation data were provided in these publications. The S97Y variant was not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Although the S97Y variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties, and this residue is not conserved, in silico analysis predicts this variant is probably damaging to the protein structure/function. Moreover, electrophoresis gradient assays found that S97Y altered the stability of TTR tetramers (Altland et al., 2007). - |
not specified Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 02, 2018 | The TTR c.290C>A; p.Ser97Tyr variant (rs121918071), also known as Ser77Tyr, is reported in the literature in multiple individuals and families affected with polyneuropathy and amyloidosis (Bhatia 1993, Blanco-Jerez 1998, Dohrn 2013, Fontana 2015, Mariani 2015, Reilly 1995, Satier 1990, Swiecicki 2015, Wallace 1998). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 13422), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. Functional analyses of the variant protein show reduced stability of monomers and tetramers (Altland 2007). The serine at codon 97 is moderately conserved and computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. 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. Bhatia K et al. Transthyretin gene mutations in British and French patients with amyloid neuropathy. J Neurol Neurosurg Psychiatry. 1993 Jun;56(6):694-7. Blanco-Jerez CR et al. Transthyretin Tyr77 familial amyloid polyneuropathy: a clinicopathological study of a large kindred. Muscle Nerve. 1998 Nov;21(11):1478-85. Dohrn MF et al. Diagnostic hallmarks and pitfalls in late-onset progressive transthyretin-related amyloid-neuropathy. J Neurol. 2013 Dec;260(12):3093-108. Fontana M et al. Differential Myocyte Responses in Patients with Cardiac Transthyretin Amyloidosis and Light-Chain Amyloidosis: A Cardiac MR Imaging Study. Radiology. 2015 Nov;277(2):388-97. Mariani LL et al. Genotype-phenotype correlation and course of transthyretin familial amyloid polyneuropathies in France. Ann Neurol. 2015 Dec;78(6):901-16. Reilly MM et al. Transthyretin gene analysis in European patients with suspected familial amyloid polyneuropathy. Brain. 1995 Aug;118 (Pt 4):849-56. Satier F et al. Diagnosis of familial amyloidotic polyneuropathy in France. Clin Genet. 1990 Dec;38(6):469-73. Swiecicki PL et al. Hereditary ATTR amyloidosis: a single-institution experience with 266 patients. Amyloid. 2015;22(2):123-31. Wallace MR et al. Identification of a new hereditary amyloidosis prealbumin variant, Tyr-77, and detection of the gene by DNA analysis. J Clin Invest. 1988 Jan;81(1):189-93. Zeldenrust SR. Genotype--phenotype correlation in FAP. Amyloid. 2012 Jun;19 Suppl 1:22-4. - |
Charcot-Marie-Tooth disease Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics Laboratory, London Health Sciences Centre | - | - - |
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 | Nov 15, 2021 | - - |
Cardiovascular phenotype Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 14, 2022 | The p.S97Y pathogenic mutation (also known as c.290C>A and S77Y), located in coding exon 3 of the TTR gene, results from a C to A substitution at nucleotide position 290. The serine at codon 97 is replaced by tyrosine, an amino acid with dissimilar properties. This mutation has been identified in numerous individuals with TTR amyloidosis (Wallace MR et al. J. Clin. Invest., 1988 Jan;81:189-93; Blanco-Jerez CR et al. Muscle Nerve, 1998 Nov;21:1478-85; Mariani LL et al. Ann. Neurol., 2015 Dec;78:901-16; Rowczenio D et al. Hum. Mutat., 2019 Jan;40:90-96). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;M;.;.
PrimateAI
Uncertain
T
PROVEAN
Uncertain
.;D;.;.
REVEL
Pathogenic
Sift
Uncertain
.;D;.;.
Sift4G
Benign
.;T;D;D
Polyphen
P;P;.;.
Vest4
0.61, 0.63, 0.85
MutPred
Loss of methylation at K100 (P = 0.0681);Loss of methylation at K100 (P = 0.0681);Loss of methylation at K100 (P = 0.0681);Loss of methylation at K100 (P = 0.0681);
MVP
0.97
MPC
1.5
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