ClinVar Genomic variation as it relates to human health
NM_000371.4(TTR):c.290C>A (p.Ser97Tyr)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000371.4(TTR):c.290C>A (p.Ser97Tyr)
Variation ID: 13422 Accession: VCV000013422.21
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q12.1 18: 31595209 (GRCh38) [ NCBI UCSC ] 18: 29175172 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Aug 29, 2016 Feb 20, 2024 Jan 5, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000371.4:c.290C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000362.1:p.Ser97Tyr missense NC_000018.10:g.31595209C>A NC_000018.9:g.29175172C>A NG_009490.1:g.8443C>A LRG_416:g.8443C>A LRG_416t1:c.290C>A LRG_416p1:p.Ser97Tyr P02766:p.Ser97Tyr - Protein change
- S97Y
- Other names
- S77Y
- Canonical SPDI
- NC_000018.10:31595208:C:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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TTR | - | - |
GRCh38 GRCh37 |
369 | 413 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 5, 2024 | RCV000014364.27 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Sep 19, 2023 | RCV000519257.4 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV001173289.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Nov 15, 2021 | RCV002504783.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 2, 2018 | RCV001000742.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 14, 2022 | RCV002433454.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Apr 15, 2016)
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criteria provided, single submitter
Method: clinical testing
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Familial amyloid neuropathy
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000696623.1
First in ClinVar: Aug 29, 2016 Last updated: Aug 29, 2016 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease
Affected status: yes
Allele origin:
germline
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Molecular Genetics Laboratory, London Health Sciences Centre
Accession: SCV001336373.1
First in ClinVar: Jun 14, 2020 Last updated: Jun 14, 2020 |
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Likely pathogenic
(Nov 15, 2021)
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criteria provided, single submitter
Method: clinical testing
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Familial amyloid neuropathy
Carpal tunnel syndrome 1 Hyperthyroxinemia, dystransthyretinemic
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002804467.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Jan 05, 2024)
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criteria provided, single submitter
Method: clinical testing
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Familial amyloid neuropathy
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000814489.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 20, 2024 |
Comment:
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). … (more)
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. (less)
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Pathogenic
(Jul 09, 2018)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000616907.2
First in ClinVar: Dec 19, 2017 Last updated: Apr 17, 2019 |
Comment:
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 … (more)
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). (less)
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Pathogenic
(Aug 02, 2018)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001157789.1
First in ClinVar: Feb 10, 2020 Last updated: Feb 10, 2020 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Apr 14, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002751911.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
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 … (more)
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. (less)
Number of individuals with the variant: 1
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Pathogenic
(Sep 19, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics Inc
Accession: SCV002771672.2
First in ClinVar: Dec 31, 2022 Last updated: Jan 26, 2024 |
Comment:
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 … (more)
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). (less)
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Pathogenic
(Nov 01, 1998)
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no assertion criteria provided
Method: literature only
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AMYLOIDOSIS, HEREDITARY, TRANSTHYRETIN-RELATED
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000034613.3
First in ClinVar: Apr 04, 2013 Last updated: Aug 29, 2016 |
Comment on evidence:
Wallace et al. (1986) described a prealbumin variant associated with autosomal dominant amyloidosis (105210) in an American patient of German ancestry living in Wisconsin. This … (more)
Wallace et al. (1986) described a prealbumin variant associated with autosomal dominant amyloidosis (105210) in an American patient of German ancestry living in Wisconsin. This involved substitution of tyrosine for serine at position 77 (S77Y) resulting from a C-to-A mutation in that codon. Using the restriction enzyme SspI and a specifically tailored genomic prealbumin oligonucleotide probe, Wallace et al. (1986, 1988) detected a single-nucleotide change in codon 77 of the variant prealbumin gene. Satier et al. (1990) found the same mutation in a family from Picardy, which is located in northern France, east of Normandy. Clinical onset was in the fifth and sixth decades with decreased sensation in the lower limbs followed by involvement of the arms. Motor changes appeared later. Cardiac involvement with congestive heart failure and arrhythmias was the cause of death. They stated that the American family of German origin was living in Illinois and that another American family with French Huguenot ancestors had been found with the tyr77 mutation. Amyloidosis resulting from this variant has been referred to as the Illinois/German type (Wallace et al., 1988). After the met30 mutation (176300.0001), the tyr77 mutation is the most prevalent. Blanco-Jerez et al. (1998) presented clinical and pathologic features of an extensive Spanish family with the tyr77 mutation of TTR. Twelve individuals over 4 generations were affected. They found that an initial and sometimes prolonged carpal tunnel syndrome, beginning between the sixth and seventh decades, characterized the tyr77 mutation. In most cases, this evolved to generalized peripheral nerve involvement, restrictive cardiomyopathy, and intestinal malabsorption. Blanco-Jerez et al. (1998) suggested that, although survival with the tyr77 mutation is usually high, there are progressive cases that should be candidates for liver transplant, before severe impairment develops. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Upper limb onset of hereditary transthyretin amyloidosis is common in non-endemic areas. | Théaudin M | European journal of neurology | 2019 | PMID: 30350904 |
Analysis of the TTR gene in the investigation of amyloidosis: A 25-year single UK center experience. | Rowczenio D | Human mutation | 2019 | PMID: 30328212 |
Prevalence and clinical phenotype of hereditary transthyretin amyloid cardiomyopathy in patients with increased left ventricular wall thickness. | Damy T | European heart journal | 2016 | PMID: 26537620 |
A study of the neuropathy associated with transthyretin amyloidosis (ATTR) in the UK. | Carr AS | Journal of neurology, neurosurgery, and psychiatry | 2016 | PMID: 26243339 |
Genotype-phenotype correlation and course of transthyretin familial amyloid polyneuropathies in France. | Mariani LL | Annals of neurology | 2015 | PMID: 26369527 |
Hereditary ATTR amyloidosis: a single-institution experience with 266 patients. | Swiecicki PL | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 2015 | PMID: 26017327 |
Differential Myocyte Responses in Patients with Cardiac Transthyretin Amyloidosis and Light-Chain Amyloidosis: A Cardiac MR Imaging Study. | Fontana M | Radiology | 2015 | PMID: 25997029 |
Clinical and genetic findings in eight Israeli patients with transthyretin-associated familial amyloid polyneuropathy. | Leibou L | The Israel Medical Association journal : IMAJ | 2012 | PMID: 23240369 |
Genotype--phenotype correlation in FAP. | Zeldenrust SR | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 2012 | PMID: 22620962 |
Genetic microheterogeneity of human transthyretin detected by IEF. | Altland K | Electrophoresis | 2007 | PMID: 17503405 |
Extended phenotype in the transthyretin Tyr77 familial amyloid polyneuropathy. | Lossos A | European neurology | 2005 | PMID: 15753613 |
Transthyretin Tyr77 familial amyloid polyneuropathy: a clinicopathological study of a large kindred. | Blanco-Jerez CR | Muscle & nerve | 1998 | PMID: 9771673 |
Genotypic-phenotypic variations in a series of 65 patients with familial amyloid polyneuropathy. | Planté-Bordeneuve V | Neurology | 1998 | PMID: 9748014 |
Transthyretin gene analysis in European patients with suspected familial amyloid polyneuropathy. | Reilly MM | Brain : a journal of neurology | 1995 | PMID: 7655883 |
Familial amyloid polyneuropathy (TTR ala 60) in north west Ireland: a clinical, genetic, and epidemiological study. | Reilly MM | Journal of neurology, neurosurgery, and psychiatry | 1995 | PMID: 7608709 |
Transthyretin gene mutations in British and French patients with amyloid neuropathy. | Bhatia K | Journal of neurology, neurosurgery, and psychiatry | 1993 | PMID: 8509786 |
A new transthyretin variant from a patient with familial amyloidotic polyneuropathy has asparagine substituted for histidine at position 90. | Skare JC | Clinical genetics | 1991 | PMID: 1997217 |
Diagnosis of familial amyloidotic polyneuropathy in France. | Satier F | Clinical genetics | 1990 | PMID: 1981182 |
Identification of a new hereditary amyloidosis prealbumin variant, Tyr-77, and detection of the gene by DNA analysis. | Wallace MR | The Journal of clinical investigation | 1988 | PMID: 2891727 |
A DNA test for Indiana/Swiss hereditary amyloidosis (FAP II). | Wallace MR | American journal of human genetics | 1988 | PMID: 2840822 |
Molecular detection of carriers of hereditary amyloidosis in a Swedish-American family. | Wallace MR | American journal of medical genetics | 1986 | PMID: 2877582 |
Wallace, M. R., Dwulet, F. E., Williams, E. C., Conneally, P. M., Benson, M. D. Identification of a new prealbumin variant, TYR-77, associated with autosomal dominant amyloidosis. (Abstract) Am. J. Hum. Genet. 39: A22, 1986. | - | - | - | - |
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Text-mined citations for rs121918071 ...
HelpRecord last updated Apr 15, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.