ClinVar Genomic variation as it relates to human health
NM_000371.4(TTR):c.349G>T (p.Ala117Ser)
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
-
NM_000371.4(TTR):c.349G>T (p.Ala117Ser)
Variation ID: 13468 Accession: VCV000013468.14
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 18q12.1 18: 31598580 (GRCh38) [ NCBI UCSC ] 18: 29178543 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Jun 3, 2016 Feb 14, 2024 Jan 24, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000371.4:c.349G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000362.1:p.Ala117Ser missense NC_000018.10:g.31598580G>T NC_000018.9:g.29178543G>T NG_009490.1:g.11814G>T LRG_416:g.11814G>T LRG_416t1:c.349G>T LRG_416p1:p.Ala117Ser P02766:p.Ala117Ser - Protein change
- A117S
- Other names
- A97S
- Canonical SPDI
- NC_000018.10:31598579:G:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
---|---|---|---|---|---|---|
HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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. |
|||
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
---|---|---|---|---|
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Jan 24, 2024 | RCV000014410.35 | |
Likely pathogenic (2) |
criteria provided, single submitter
|
Feb 15, 2017 | RCV000223869.3 | |
Pathogenic (1) |
criteria provided, single submitter
|
May 11, 2022 | RCV002496359.1 | |
Pathogenic (1) |
criteria provided, single submitter
|
Mar 3, 2021 | RCV002453260.1 |
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. |
|
---|---|---|---|---|---|
Pathogenic
(Feb 14, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Familial amyloid neuropathy
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000696629.1
First in ClinVar: Aug 29, 2016 Last updated: Aug 29, 2016 |
Comment:
Variant summary: The TTR c.349G>T (p.Ala117Ser) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant … (more)
Variant summary: The TTR c.349G>T (p.Ala117Ser) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). 5/5 splice prediction tools predict no significant impact on normal splicing, however, 3/5 tools predict that this variant may remove a cryptic 3' splicing acceptor site. ESE finder predicts that this variant may affect multiple ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant has been reported in multiple ATTR patients in Chinese population and is absent in 121750 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
|
|
Pathogenic
(May 18, 2010)
|
criteria provided, single submitter
Method: clinical testing
|
Familial amyloid neuropathy
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000203977.5
First in ClinVar: Jan 31, 2015 Last updated: Aug 13, 2019 |
Number of individuals with the variant: 1
|
|
Pathogenic
(May 11, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Familial amyloid neuropathy
Carpal tunnel syndrome 1 Hyperthyroxinemia, dystransthyretinemic
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002810197.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
Pathogenic
(Jan 24, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial amyloid neuropathy
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000769150.8
First in ClinVar: Aug 29, 2016 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 117 of the TTR protein (p.Ala117Ser). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 117 of the TTR protein (p.Ala117Ser). This variant is present in population databases (rs267607161, gnomAD 0.01%). This missense change has been observed in individuals with transthyretin amyloidosis (PMID: 10611950, 18022643, 20697105, 22412233, 23713495). This variant is also known as Ala97Ser. ClinVar contains an entry for this variant (Variation ID: 13468). 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 95%. Experimental studies have shown that this missense change affects TTR function (PMID: 20697105). This variant disrupts the p.Ala117 (also known as p.Ala97) amino acid residue in TTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8133316, 10611950, 14986482, 20209591). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Likely pathogenic
(Feb 15, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Athena Diagnostics Inc
Accession: SCV000616215.1
First in ClinVar: Jun 03, 2016 Last updated: Jun 03, 2016 |
|
|
Pathogenic
(Mar 03, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002612928.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.A117S pathogenic mutation (also known as c.349G>T and A97S) located in coding exon 4 of the TTR gene, results from a G to T … (more)
The p.A117S pathogenic mutation (also known as c.349G>T and A97S) located in coding exon 4 of the TTR gene, results from a G to T substitution at nucleotide position 349. The alanine at codon 117 is replaced by serine, an amino acid with similar properties. This variant has been reported in multiple individuals with TTR amyloidosis (Tachibana N et al. Amyloid, 1999 Dec;6:282-8; Yang NC et al. Neurology, 2010 Aug;75:532-8; Hsu HC et al. BMC Neurol, 2017 Sep;17:178; Chen Q et al. Mol. Neurobiol., 2018 Jun;55:4911-4917; Yuan Z et al. J Clin Neurosci, 2019 Feb;60:164-166; Chao HC et al. Ann Clin Transl Neurol, 2019 May;6:913-922; Liao CH et al. Diagnostics (Basel), 2019 Apr;9:). This variant was proposed as a hot spot in the Chinese-Taiwanese population based on 5 unrelated individuals of this ethnic group with familial TTR and a clinical picture including carpal tunnel syndrome, late-onset polyneuropathy, and autonomic dysfunction with cardiac involvement (Liu YT et al. J. Neurol. Sci., 2008 Apr;267:91-9). Mouse heterozygous knock-in models demonstrated consistent neuropathy phenotype and amyloid deposits confirmed by anti-TTR immunohistochemistry (Kan HW et al. Neuropathol. Appl. Neurobiol., 2018 12;44:673-686). A disease-causing mutation, p.A117G, has been described in the same codon in individuals with TTR amyloidosis (Barreiros AP et al. Liver Transpl., 2010 Mar;16:314-23; Koike H et al. J. Neurol. Sci., 2018 Nov;394:99-106). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Not provided
Affected status: not provided
Allele origin:
germline
|
Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000280560.1
First in ClinVar: Jun 03, 2016 Last updated: Jun 03, 2016 |
Comment:
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case … (more)
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. This variant has been previously reported in multiple families with amyloidosis. The variant was first reported by Tachibana et al (1999) in a cohort of Chinese patients with familial amyloid polyneuropathy (FAP). Unfortunately only the abstract is available and this does not list segregation, functional, or control data. Lachmann et al (2000) briefly reported this variant in a family in which two brothers with progressive peripheral and autonomic neuropathy as well as subclinical cardiac and renal amyloid deposition. The variant was observed in two Chinese-Taiwanese brothers who presented with amyloidosis at ages 56 and 60. Liu et al (2008) reported the variant in five unrelated Chinese-Taiwanese patients between the ages of 55 and 67 with amyloidosis. The phenotype included late-onset polyneuropathy, carpel tunnel syndrome, autonomic dysfunction, and cardiac involvement. Interestingly, haplotype analysis was inconsistent with a founder effect. Yang et al (2010) observed the variant in 19 unrelated Taiwanese patients with polyneuropathy between the ages of 48 and 68. Another variant at the same codon has also been reported in association with amyloidosis: p.Ala97Gly (Yasude et al 1994). In silico analysis with Polyphen2 predicts the variant to be possibly damaging. The Alanine at codon 97 is completely conserved as are the neighboring residues. Lachmann et al (2000) reported the variant was absent in at least 50 control individuals. Liu et al (2008) did not observe it in 100 Chinese control individuals. Yang et al (2010) reported the variant was not seen in their sample of 365 Taiwanese controls, for a total of 515 control individuals. (less)
|
|
Pathogenic
(Aug 10, 2010)
|
no assertion criteria provided
Method: literature only
|
AMYLOIDOSIS, HEREDITARY, TRANSTHYRETIN-RELATED
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000034659.2
First in ClinVar: Apr 04, 2013 Last updated: Aug 29, 2016 |
Comment on evidence:
In 5 unrelated Chinese Taiwanese patients with TTR-related amyloidosis (105210), Liu et al. (2008) identified a heterozygous 349G-T transversion in exon 4 of the TTR … (more)
In 5 unrelated Chinese Taiwanese patients with TTR-related amyloidosis (105210), Liu et al. (2008) identified a heterozygous 349G-T transversion in exon 4 of the TTR gene, resulting in an ala97-to-ser (A97S) substitution in a highly conserved residue. The phenotype consisted of late-onset polyneuropathy, carpal tunnel syndrome, and autonomic dysfunction particularly affecting the gastrointestinal tract. Heart was the most frequently involved vital organ. Haplotype analysis suggested independent origins for the mutation. Yang et al. (2010) identified the A97S mutation in 19 unrelated Taiwanese patients with a generalized disabling polyneuropathy. The age at symptom onset ranged from 48 to 68 years, and severe disease progression occurred within 5 years. All had motor, sensory, and autonomic symptoms with loss of sensation to thermal stimuli and loss of proprioception. Sural nerve biopsies showed an eosinophilic deposition of TTR-positive amyloid and a pattern of axonal degeneration with loss of large and small myelinated fibers. Skin biopsies of all patients showed a severe loss of intraepidermal nerve fiber density and sparse degenerated fragmented dermal nerve fibers compared to controls; the degree of loss of these fibers correlated with clinical severity. The mutation was not found in 365 Taiwanese controls. (less)
|
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 |
---|---|---|---|---|
Assessment of cardiac amyloidosis with (99m)Tc-pyrophosphate (PYP) quantitative SPECT. | Ren C | EJNMMI physics | 2021 | PMID: 33411102 |
Clinical and genetic features of transthyretin-related familial amyloid polyneuropathy in China. | Liu L | Chinese medical journal | 2020 | PMID: 32925285 |
Cellular secretion and cytotoxicity of transthyretin mutant proteins underlie late-onset amyloidosis and neurodegeneration. | Ibrahim RB | Cellular and molecular life sciences : CMLS | 2020 | PMID: 31728576 |
Noninvasive diagnosis of hereditary transthyretin-related cardiac amyloidosis: A case report. | Qin J | Medicine | 2019 | PMID: 31348283 |
Ala97Ser mutation is common among ethnic Chinese Malaysians with transthyretin familial amyloid polyneuropathy. | Low SC | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 2019 | PMID: 31343308 |
Clinical and genetic profiles of hereditary transthyretin amyloidosis in Taiwan. | Chao HC | Annals of clinical and translational neurology | 2019 | PMID: 31139689 |
Preimplantation Genetic Diagnosis of Neurodegenerative Diseases: Review of Methodologies and Report of Our Experience as a Regional Reference Laboratory. | Liao CH | Diagnostics (Basel, Switzerland) | 2019 | PMID: 31018485 |
Estimating the prevalence of allelic variants in the transthyretin gene by analysing large-scale sequencing data. | Lahuerta Pueyo C | European journal of human genetics : EJHG | 2019 | PMID: 30683924 |
Familial amyloid polyneuropathy with chronic paroxysmal dry cough in Mainland China: A Chinese family with a proven heterozygous missense mutation c.349G>T in the transthyretin gene. | Yuan Z | Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia | 2019 | PMID: 30361054 |
Characteristics of South Korean Patients with Hereditary Transthyretin Amyloidosis. | Choi K | Journal of clinical neurology (Seoul, Korea) | 2018 | PMID: 30198232 |
Sensory nerve degeneration in a mouse model mimicking early manifestations of familial amyloid polyneuropathy due to transthyretin Ala97Ser. | Kan HW | Neuropathology and applied neurobiology | 2018 | PMID: 29423915 |
A Missense Variant p.Ala117Ser in the Transthyretin Gene of a Han Chinese Family with Familial Amyloid Polyneuropathy. | Chen Q | Molecular neurobiology | 2018 | PMID: 28762097 |
Phenotypic expressions of hereditary Transthyretin Ala97Ser related Amyloidosis (ATTR) in Taiwanese. | Hsu HC | BMC neurology | 2017 | PMID: 28882124 |
Mechanism of Action and Clinical Application of Tafamidis in Hereditary Transthyretin Amyloidosis. | Coelho T | Neurology and therapy | 2016 | PMID: 26894299 |
The Temporal Profiles of Changes in Nerve Excitability Indices in Familial Amyloid Polyneuropathy. | Lai HJ | PloS one | 2015 | PMID: 26529114 |
Hereditary Transthyretin Amyloidosis in Eight Chinese Families. | Meng LC | Chinese medical journal | 2015 | PMID: 26521788 |
Sudomotor innervation in transthyretin amyloid neuropathy: Pathology and functional correlates. | Chao CC | Annals of neurology | 2015 | PMID: 25973863 |
Amyloid fibrils containing fragmented ATTR may be the standard fibril composition in ATTR amyloidosis. | Ihse E | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 2013 | PMID: 23713495 |
Direct tissue evaluation via immunofluorescence: in the diagnosis of hereditary transthyretin cardiac amyloidosis. | Fradley MG | Texas Heart Institute journal | 2012 | PMID: 22412233 |
Mass spectrometric-based proteomic analysis of amyloid neuropathy type in nerve tissue. | Klein CJ | Archives of neurology | 2011 | PMID: 20937937 |
Pathology and functional diagnosis of small-fiber painful neuropathy. | Hsieh ST | Acta neurologica Taiwanica | 2010 | PMID: 20714957 |
Clinical presentations and skin denervation in amyloid neuropathy due to transthyretin Ala97Ser. | Yang NC | Neurology | 2010 | PMID: 20697105 |
Liver transplantation and combined liver-heart transplantation in patients with familial amyloid polyneuropathy: a single-center experience. | Barreiros AP | Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society | 2010 | PMID: 20209591 |
Transthyretin Ala97Ser in Chinese-Taiwanese patients with familial amyloid polyneuropathy: genetic studies and phenotype expression. | Liu YT | Journal of the neurological sciences | 2008 | PMID: 18022643 |
The hereditary amyloidoses. | Benson MD | Best practice & research. Clinical rheumatology | 2003 | PMID: 15123043 |
Clinical and pathological studies of cardiac amyloidosis in transthyretin type familial amyloid polyneuropathy. | Hattori T | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 2003 | PMID: 14986482 |
Tabulation of human transthyretin (TTR) variants, 2003. | Connors LH | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 2003 | PMID: 14640030 |
Transthyretin mutations in hyperthyroxinemia and amyloid diseases. | Saraiva MJ | Human mutation | 2001 | PMID: 11385707 |
Transthyretin Ala97Ser is associated with familial amyloidotic polyneuropathy in a Chinese-Taiwanese family. | Lachmann HJ | Human mutation | 2000 | PMID: 10923048 |
Usefulness of MALDI/TOF mass spectrometry of immunoprecipitated serum variant transthyretin in the diagnosis of familial amyloid polyneuropathy. | Tachibana N | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 1999 | PMID: 10611950 |
Familial amyloidotic polyneuropathy with late-onset and well-preserved autonomic function: a Japanese kindred with novel mutant transthyretin (Ala97 to Gly). | Yasuda T | Journal of the neurological sciences | 1994 | PMID: 8133316 |
click to load more click to collapse |
Text-mined citations for rs267607161 ...
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.