ClinVar Genomic variation as it relates to human health
NM_000371.4(TTR):c.118G>A (p.Val40Ile)
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.118G>A (p.Val40Ile)
Variation ID: 13455 Accession: VCV000013455.26
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q12.1 18: 31592944 (GRCh38) [ NCBI UCSC ] 18: 29172907 (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 Dec 19, 2017 Apr 15, 2024 Oct 10, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000371.4:c.118G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000362.1:p.Val40Ile missense NC_000018.10:g.31592944G>A NC_000018.9:g.29172907G>A NG_009490.1:g.6178G>A LRG_416:g.6178G>A LRG_416t1:c.118G>A LRG_416p1:p.Val40Ile P02766:p.Val40Ile - Protein change
- V40I
- Other names
- V20I
- p.V40I:GTC>ATC
- Canonical SPDI
- NC_000018.10:31592943:G: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.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
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
Help
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, single submitter
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Oct 10, 2023 | RCV000014397.40 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Dec 1, 2021 | RCV000159420.24 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 5, 2022 | RCV002336083.8 |
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
(Aug 24, 2017)
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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: SCV000209366.13
First in ClinVar: Feb 24, 2015 Last updated: Dec 19, 2017 |
Comment:
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 … (more)
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). (less)
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Pathogenic
(Apr 05, 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: SCV002640431.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.V40I pathogenic mutation (also known as c.118G>A), located in coding exon 2 of the TTR gene, results from a G to A substitution at … (more)
The p.V40I pathogenic mutation (also known as c.118G>A), located in coding exon 2 of the TTR gene, results from a G to A substitution at nucleotide position 118. The valine at codon 40 is replaced by isoleucine, an amino acid with highly similar properties. This pathogenic mutation (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 DE et al. Proc. Natl. Acad. Sci. U.S.A., 1996 Jun;93:6302-7). 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 K et al. Electrophoresis, 2007 Jun;28:2053-64). This pathogenic mutation 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 DR et al. Hum. Mutat., 1997;9:83-5). Another study in a cohort of 59 related individuals from a small village in southern Germany in which this mutation was prevalent concluded that this mutation results in a predominantly cardiac phenotype with high penetrance and late onset of symptoms (Bauer R et al. Amyloid, 2014 Dec;21:267-75). 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 D et al. Hum Mutat. 2019;40(1):90-96). 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
(Feb 24, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV002048940.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Oct 10, 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: SCV001207082.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
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). … (more)
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). 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. 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. (less)
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Pathogenic
(Dec 01, 2021)
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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: SCV002563459.10
First in ClinVar: Aug 23, 2022 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Feb 13, 1997)
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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: SCV000034646.3
First in ClinVar: Apr 04, 2013 Last updated: Jun 18, 2018 |
Comment on evidence:
In a German 3-generation family, Jenne et al. (1996) identified a 'new' amyloidogenic val20-to-ile (V20I) mutation in the TTR gene. The index patient suffered from … (more)
In a German 3-generation family, Jenne et al. (1996) identified a 'new' amyloidogenic val20-to-ile (V20I) mutation in the TTR gene. The index patient suffered from severe amyloid cardiomyopathy (105210) at the age of 60. Conformational stability and unfolding behavior of the mutant ile20 monomer in urea gradients was found to be almost indistinguishable from that of wildtype TTR. In contrast, tetramer stability was significantly reduced in agreement with the expected change in the interactions between 2 opposing dimers via the side chain of ile20. The TTR molecule consists of 4 identical, noncovalently linked subunits of 127 amino acids each that form a pair of dimers in the plasma protein complex. The observations of Jenne et al. (1996) led them to conclude that amyloidogenic amino acid substitutions in TTR facilitate the conversion of tetrameric TTR complexes into conformational intermediates of the TTR folding pathway that have an intrinsic amyloidogenic potential. Independently, Jacobson et al. (1997) found the V20I mutation in a 50-year-old white man with a 2-year history of exertional epigastric distress, occasional lightheadedness without syncope, and a 1-year history of symptoms consistent with carpal tunnel syndrome. The patient had previously been diagnosed with congestive heart failure and treated with a diuretic. The patient showed mild postural hypotension. Orthotopic cardiac transplantation was performed. The patient's mother had bilateral carpal tunnel release at age 70 and symptoms and findings consistent with cardiac amyloidosis in her late seventies. Three of her brothers had died of heart failure after age 70. (less)
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Pathogenic
(Feb 21, 2019)
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no assertion criteria provided
Method: clinical testing
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Familial Transthyretin Amyloidosis
Affected status: yes
Allele origin:
germline
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Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals
Accession: SCV001338805.1
First in ClinVar: Jun 18, 2020 Last updated: Jun 18, 2020 |
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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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Analysis of the TTR gene in the investigation of amyloidosis: A 25-year single UK center experience. | Rowczenio D | Human mutation | 2019 | PMID: 30328212 |
The "Wagshurst study": p.Val40Ile transthyretin gene variant causes late-onset cardiomyopathy. | Bauer R | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 2014 | PMID: 25291558 |
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 |
Genetic microheterogeneity of human transthyretin detected by IEF. | Altland K | Electrophoresis | 2007 | PMID: 17503405 |
The biological and chemical basis for tissue-selective amyloid disease. | Sekijima Y | Cell | 2005 | PMID: 15820680 |
Variant-sequence transthyretin (isoleucine 122) in late-onset cardiac amyloidosis in black Americans. | Jacobson DR | The New England journal of medicine | 1997 | PMID: 9017939 |
Transthyretin ILE20, a new variant associated with late-onset cardiac amyloidosis. | Jacobson DR | Human mutation | 1997 | PMID: 8990019 |
A new isoleucine substitution of Val-20 in transthyretin tetramers selectively impairs dimer-dimer contacts and causes systemic amyloidosis. | Jenne DE | Proceedings of the National Academy of Sciences of the United States of America | 1996 | PMID: 8692810 |
Text-mined citations for rs121918093 ...
HelpRecord last updated Apr 20, 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.