ClinVar Genomic variation as it relates to human health
NM_000371.4(TTR):c.379A>G (p.Ile127Val)
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.379A>G (p.Ile127Val)
Variation ID: 13450 Accession: VCV000013450.37
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q12.1 18: 31598610 (GRCh38) [ NCBI UCSC ] 18: 29178573 (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 Apr 4, 2013 Apr 15, 2024 Dec 13, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000371.4:c.379A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000362.1:p.Ile127Val missense NC_000018.10:g.31598610A>G NC_000018.9:g.29178573A>G NG_009490.1:g.11844A>G LRG_416:g.11844A>G LRG_416t1:c.379A>G LRG_416p1:p.Ile127Val P02766:p.Ile127Val - Protein change
- I127V
- Other names
- I107V
- Canonical SPDI
- NC_000018.10:31598609:A:G
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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
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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 (4) |
criteria provided, multiple submitters, no conflicts
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Dec 13, 2023 | RCV000014392.27 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Oct 1, 2023 | RCV001090344.19 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 10, 2022 | RCV002354161.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 9, 2021 | RCV002504784.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 22, 2022 | RCV003458163.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Mar 1, 2017 | RCV000506089.9 |
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
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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
(Feb 26, 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: SCV000696632.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
Comment:
Variant summary: The TTR c.379A>G variant affects a conserved nucleotide, resulting in amino acid change from Ile to Val. 3/4 in-silico tools predict this variant … (more)
Variant summary: The TTR c.379A>G variant affects a conserved nucleotide, resulting in amino acid change from Ile to Val. 3/4 in-silico tools predict this variant to be benign (SNPs&GO not captured due to low reliability index). However, functional studies indicate that TTRI107V dimers and tetramers decreased stability compared to controls. This variant is not found in 121416 control chromosomes, but has been cited in numerous ATTR patients from various ethnicities. Taken together, this is a disease variant and was classified as pathogenic. (less)
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Pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001446722.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Sensory axonal neuropathy (present) , Hand muscle atrophy (present)
Sex: male
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Pathogenic
(Sep 09, 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: SCV002813237.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Feb 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary amyloidosis
Affected status: unknown
Allele origin:
germline
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Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV004183383.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
ACMG classification criteria: PS3 strong, PS4 strong, PM2 moderated
Geographic origin: Brazil
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Pathogenic
(Dec 13, 2023)
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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: SCV000769146.7
First in ClinVar: Oct 11, 2015 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 127 of the TTR protein (p.Ile127Val). … (more)
This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 127 of the TTR protein (p.Ile127Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with amyloidosis (PMID: 7914929, 8081397, 9748014, 20209591, 24101130, 26537620, 27025994, 27066555). This variant is also known as p.Ile107Val. ClinVar contains an entry for this variant (Variation ID: 13450). 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: 17503405). This variant disrupts the p.Ile127 amino acid residue in TTR. Other variant(s) that disrupt this residue have been observed in individuals with TTR-related conditions (PMID: 22745357, 24480837), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Oct 01, 2023)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001245843.18
First in ClinVar: May 12, 2020 Last updated: Apr 15, 2024 |
Comment:
TTR: PM2, PM5, PS3:Moderate, PS4:Supporting
Number of individuals with the variant: 9
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Likely pathogenic
(Mar 01, 2017)
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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: SCV000605507.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
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Pathogenic
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Familial amyloid neuropathy
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001140874.1
First in ClinVar: Jan 11, 2020 Last updated: Jan 11, 2020 |
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Pathogenic
(Mar 10, 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: SCV002622727.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.I127V pathogenic mutation (also known as c.379A>G and p.I107V), located in coding exon 4 of the TTR gene, results from an A to G … (more)
The p.I127V pathogenic mutation (also known as c.379A>G and p.I107V), located in coding exon 4 of the TTR gene, results from an A to G substitution at nucleotide position 379. The isoleucine at codon 127 is replaced by valine, an amino acid with highly similar properties. This variant has been detected in multiple individuals with TTR-related amyloidosis (Jacobson DR et al. Hum. Mutat., 1994;3:399-401; Planté-Bordeneuve V et al. Neurology, 1998 Sep;51:708-14; Damy T et al. Eur. Heart J., 2016 06;37:1826-34; Kuzume D et al. Rinsho Shinkeigaku, 2016 04;56:277-80). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Functional studies indicate that this variant results in unstable interaction between transthyretin tetramers (Altland K et al. Electrophoresis, 2007 Jun;28:2053-64). Two different alterations located at the same amino acid position, p.I127F (c.379A>T, historically known as p.I107F) and p.I127M (c.381T>G, historically known as p.I107M), have also been detected in individuals with TTR-related amyloidosis (Cappellari M et al. J. Peripher. Nerv. Syst., 2011 Jun;16:119-29; Lv W et al. Eye (Lond), 2014 Apr;28:452-8). 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
(Oct 26, 2022)
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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: SCV002588084.2
First in ClinVar: Nov 05, 2022 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate that TTR dimers from individuals heterozygous for TTRI127V are less stable than dimers from wild type individuals (Atland K et al., … (more)
Published functional studies demonstrate that TTR dimers from individuals heterozygous for TTRI127V are less stable than dimers from wild type individuals (Atland K et al., 2007); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as I107V; This variant is associated with the following publications: (PMID: 22301727, 8081397, 30306720, 20209591, 22745357, 19781421, 12039669, 7914929, 24101130, 32723050, 33481097, 33188503, 33844361, 34668655, 34602081, 34746851, 33283548, 34391735, 35665045, 35599006, 35417510, 35346209, 35331287, ScirpaR2022, 17443043, 9748014, 27025994, 27066555, 34658264, 26537620, 29520877, 26656838, 34440326, 35637921, 35580748, 17503405) (less)
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Pathogenic
(Jul 21, 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: SCV001476395.2
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2024 |
Comment:
This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. This variant has not been reported in large, multi-ethnic … (more)
This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. This variant has not been reported in large, multi-ethnic general populations. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) In some published literature, this variant is referred to as p.Ile107Val. (less)
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Pathogenic
(May 01, 1994)
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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: SCV000034641.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In 2 American patients of German descent with amyloid polyneuropathy (105210), Uemichi et al. (1994) identified heterozygosity for an ATT (isoleucine) to GTT (valine) transition … (more)
In 2 American patients of German descent with amyloid polyneuropathy (105210), Uemichi et al. (1994) identified heterozygosity for an ATT (isoleucine) to GTT (valine) transition in the codon corresponding to amino acid 107 of mature TTR (I107V). The mutation created a new MaeIII restriction site which could be used in diagnosis. Although clinical and family information were limited, Uemichi et al. (1994) indicated that both patients had had a diagnosis of carpal tunnel syndrome at the age of 56 and subsequently developed polyneuropathy in the legs. The father of 1 of the patients had died at the age of 60 of a similar illness, and necropsy showed amyloidosis. (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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Cerebral Ischemic Events: An Overlooked Complication of Transthyretin Cardiac Amyloidosis in Afro-Caribbean Patients. | Banydeen R | Frontiers in neurology | 2022 | PMID: 35665045 |
A Rare Case of I127V Heterozygous Transthyretin Amyloidosis With Atypical Transthoracic Echocardiogram Findings Presenting As Upper Extremity Sensorimotor Polyneuropathy. | Ostojic M | Cureus | 2022 | PMID: 35637921 |
Ophthalmological manifestations of hereditary transthyretin amyloidosis. | Gondim FAA | Arquivos brasileiros de oftalmologia | 2022 | PMID: 35417510 |
Genomic Screening for Pathogenic Transthyretin Variants Finds Evidence of Underdiagnosed Amyloid Cardiomyopathy From Health Records. | Carry BJ | JACC. CardioOncology | 2021 | PMID: 34746851 |
Hereditary transthyretin-related amyloidosis is frequent in polyneuropathy and cardiomyopathy of no obvious aetiology. | Skrahina V | Annals of medicine | 2021 | PMID: 34658264 |
Variant Transthyretin Amyloidosis (ATTRv) in Hungary: First Data on Epidemiology and Clinical Features. | Pozsonyi Z | Genes | 2021 | PMID: 34440326 |
Mitochondrial disease and amyloidosis in a patient with familial polyneuropathy. | Gebus O | European journal of neurology | 2018 | PMID: 30306720 |
The genetic heterogeneity of hereditary transthyretin amyloidosis in a sample of the Brazilian population. | Lavigne-Moreira C | Journal of the peripheral nervous system : JPNS | 2018 | PMID: 29520877 |
Refine penetrance estimates in the main pathogenic variants of transthyretin hereditary (familial) amyloid polyneuropathy (TTR-FAP) using a new non-parametric approach (NPSE). | Gorram F | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 2017 | PMID: 28434346 |
[A case of familial amyloid polyneuropathy (FAP ATTR Ile107Val) with proximal muscle weakness in the lower extremities]. | Kuzume D | Rinsho shinkeigaku = Clinical neurology | 2016 | PMID: 27025994 |
Survival After Transplantation in Patients With Mutations Other Than Val30Met: Extracts From the FAP World Transplant Registry. | Suhr OB | Transplantation | 2016 | PMID: 26656838 |
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 |
Tongue atrophy and fasciculations in transthyretin familial amyloid neuropathy: An ALS mimicker. | Goyal NA | Neurology. Genetics | 2015 | PMID: 27066555 |
Multimodal retinal imaging in a Chinese kindred with familial amyloid polyneuropathy secondary to transthyretin Ile107Met mutation. | Lv W | Eye (London, England) | 2014 | PMID: 24480837 |
Diagnostic hallmarks and pitfalls in late-onset progressive transthyretin-related amyloid-neuropathy. | Dohrn MF | Journal of neurology | 2013 | PMID: 24101130 |
Disease profile and differential diagnosis of hereditary transthyretin-related amyloidosis with exclusively cardiac phenotype: an Italian perspective. | Rapezzi C | European heart journal | 2013 | PMID: 22745357 |
Variable presentations of TTR-related familial amyloid polyneuropathy in seventeen patients. | Cappellari M | Journal of the peripheral nervous system : JPNS | 2011 | PMID: 21692911 |
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 |
Cardiac amyloidosis in African Americans: comparison of clinical and laboratory features of transthyretin V122I amyloidosis and immunoglobulin light chain amyloidosis. | Connors LH | American heart journal | 2009 | PMID: 19781421 |
Genetic microheterogeneity of human transthyretin detected by IEF. | Altland K | Electrophoresis | 2007 | PMID: 17503405 |
Trigger finger as an initial manifestation of familial amyloid polyneuropathy in a patient with Ile107Val TTR. | Uotani K | Internal medicine (Tokyo, Japan) | 2007 | PMID: 17443043 |
The hereditary amyloidoses. | Benson MD | Best practice & research. Clinical rheumatology | 2003 | PMID: 15123043 |
Transthyretin Val 107 in a Japanese patient with familial amyloid polyneuropathy. | Nanri K | Journal of the neurological sciences | 2002 | PMID: 12039669 |
Genotypic-phenotypic variations in a series of 65 patients with familial amyloid polyneuropathy. | Planté-Bordeneuve V | Neurology | 1998 | PMID: 9748014 |
Transthyretin VAL107, a new variant associated with familial cardiac and neuropathic amyloidosis. | Jacobson DR | Human mutation | 1994 | PMID: 8081397 |
Amyloid polyneuropathy in two German-American families: a new transthyretin variant (Val 107). | Uemichi T | Journal of medical genetics | 1994 | PMID: 7914929 |
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Text-mined citations for rs121918089 ...
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.