ClinVar Genomic variation as it relates to human health
NM_000371.4(TTR):c.190T>C (p.Phe64Leu)
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.
Likely pathogenic(2); Uncertain significance(4); Likely benign(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000371.4(TTR):c.190T>C (p.Phe64Leu)
Variation ID: 178280 Accession: VCV000178280.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q12.1 18: 31593016 (GRCh38) [ NCBI UCSC ] 18: 29172979 (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 Sep 26, 2017 Sep 16, 2024 Jun 20, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000371.4:c.190T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000362.1:p.Phe64Leu missense NC_000018.10:g.31593016T>C NC_000018.9:g.29172979T>C NG_009490.1:g.6250T>C LRG_416:g.6250T>C LRG_416t1:c.190T>C LRG_416p1:p.Phe64Leu - Protein change
- F64L
- Other names
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- Canonical SPDI
- NC_000018.10:31593015:T:C
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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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0.00020 (C)
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00004
Exome Aggregation Consortium (ExAC) 0.00006
Trans-Omics for Precision Medicine (TOPMed) 0.00016
The Genome Aggregation Database (gnomAD) 0.00019
1000 Genomes Project 0.00020
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00023
1000 Genomes Project 30x 0.00031
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 | ||
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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
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. |
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TTR | - | - |
GRCh38 GRCh37 |
374 | 421 |
Conditions - Germline
Condition
Help
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
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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. |
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Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Jun 20, 2024 | RCV000155021.9 | |
Likely benign (1) |
criteria provided, single submitter
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Dec 17, 2023 | RCV000474349.10 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Jun 14, 2023 | RCV000766993.3 | |
Likely pathogenic (1) |
criteria provided, single submitter
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- | RCV001173294.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jul 8, 2020 | RCV001798511.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jul 13, 2022 | RCV002408691.2 |
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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Uncertain significance
(Apr 06, 2021)
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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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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000204704.8
First in ClinVar: Jan 31, 2015 Last updated: May 29, 2021 |
Comment:
Variant classified as Uncertain Significance - Favor Pathogenic. The p.Phe64Leu variant in TTR has been reported in at least 17 individuals with amyloidosis, including one … (more)
Variant classified as Uncertain Significance - Favor Pathogenic. The p.Phe64Leu variant in TTR has been reported in at least 17 individuals with amyloidosis, including one homozygote and one compound heterozygote for another pathogenic TTR missesne variant which suggests that this variant may not be the primary cause of disease in this individual.(Ferlini 1996 PMID: 8721565, Comenzo 2006 PMID: 16439680, Connors 2009 PMID: 19781421, Cappellari 2011 PMID: 21692911, Klein 2011 PMID: 20937937, Rapezzi 2011 PMID: 21679902, Luigetti 2012 PMID: 22592564). It has also been reported in two individuals with hypertrophic cardiomyopathy (Walsh 2017 PMID: 27532257 Hoss 2020 PMID: 32150461, LMM data). It has been identified in 0.06% (14/24960) of African American chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 178280). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In vitro functional studies provide some evidence that this variant impacts protein function (Altland 2007 PMID: 17503405); however, these types of assays may not accurately represent biological function. Additional variants involving this codon (p.Phe64Ser and p.Phe64Tyr) have been identified in individuals with amyloidosis. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain: ACMG/AMP Criteria applied: PS4, PS3_Supporting. (less)
Number of individuals with the variant: 1
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Uncertain significance
(Jul 08, 2020)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy
Affected status: unknown
Allele origin:
germline
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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV002042741.1
First in ClinVar: Dec 29, 2021 Last updated: Dec 29, 2021 |
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Likely pathogenic
(Jun 14, 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
Accession: SCV004229419.1
First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024 |
Comment:
The frequency of this variant is statistically more frequent in affected individuals than in the general population and/or healthy controls (Genome Aggregation Database (gnomAD), Cambridge, … (more)
The frequency of this variant is statistically more frequent in affected individuals than in the general population and/or healthy controls (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant has been identified in multiple unrelated individuals with hereditary transthyretin-related amyloidosis, including individuals with cardiac transthyretin amyloidosis. In Italy, it has been suggested to be one of the most common variants associated with FAP (familial amyloidotic polyneuropathy) (PMID: 36289657). Multiple affected individuals have been reported with missense changes at this codon, suggesting this variant also causes disease. This variant is also referred to as F44L and F84L in published literature. (less)
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Uncertain significance
(Dec 15, 2016)
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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: SCV000209370.4
First in ClinVar: Feb 24, 2015 Last updated: Apr 17, 2019 |
Comment:
A variant of uncertain significance was identified in the TTR gene. The F64L variant has previously been reported in association with cardiac amyloidosis (Connors et … (more)
A variant of uncertain significance was identified in the TTR gene. The F64L variant has previously been reported in association with cardiac amyloidosis (Connors et al., 2009; Reddi et al., 2014; Rowczenio et al., 2014). F64L (reported as F44L due to alternate nomenclature) was initially reported in an African American patient with amyloidosis who also harbored a second missense variant on the opposite TTR allele (in trans) (Connors et al., 2009). The F64L (reported as F44L) variant has also been reported in a Caucasian individual with cardiac involvement in the Online Registry for Mutations in Hereditary Amyloidosis (Rowczenio et al., 2014). Additionally, this variant has also been observed in other unrelated individuals referred for cardiomyopathy genetic testing at GeneDx, and has been classified in ClinVar as a variant of uncertain significance by another clinical laboratory (ClinVar SCV000204704.5; Landrum et al., 2016). The F64L variant was not observed at a significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Other missense variants in nearby residues (W61L, E62G, E62D, A65S, A65T, A65D) and at the same residue (F64Y, F64S) have been reported in the Human Gene Mutation Database in association with amyloidosis, amylodotic polyneuropathy, and cardiomyopathy (Stenson et al., 2014); however, the pathogenicity of these variants has not been definitively determined. In addition, the F64L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Furthermore, this substitution occurs at a position where amino acids with similar properties to Phenylalanine are tolerated across species, and in silico algorithms are inconsistent in predicting an effect of this variant on protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign. (less)
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Likely 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: SCV001336378.1
First in ClinVar: Jun 14, 2020 Last updated: Jun 14, 2020 |
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Likely benign
(Jun 20, 2024)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV005204225.1
First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024 |
Comment:
Variant summary: TTR c.190T>C (p.Phe64Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign … (more)
Variant summary: TTR c.190T>C (p.Phe64Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 251466 control chromosomes, predominantly at a frequency of 0.00062 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 12 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTR causing Isolated Cardiac Amyloidosis phenotype (5e-05). c.190T>C has been reported in the literature in individuals affected with Isolated Cardiac Amyloidosis or cardiomyopathy, as well as unaffected carriers (e.g. Connors_2009, Walsh_2017, Musumeci_2020). These reports do not provide unequivocal conclusions about association of the variant with Isolated Cardiac Amyloidosis. Co-occurrence with another pathogenic variant has been reported (TTR c.424G>A, p.Val142Ile, Connors_2009), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Altland_2007). The following publications have been ascertained in the context of this evaluation (PMID: 19781421, 17503405, 27532257, 31864976). ClinVar contains an entry for this variant (Variation ID: 178280). Based on the evidence outlined above, the variant was classified as likely benign. (less)
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Likely benign
(Dec 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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Amyloidosis, hereditary systemic 1
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000541952.9
First in ClinVar: Apr 17, 2017 Last updated: Feb 14, 2024 |
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Uncertain significance
(Jul 13, 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: SCV002723277.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.F64L variant (also known as c.190T>C), located in coding exon 2 of the TTR gene, results from a T to C substitution at nucleotide … (more)
The p.F64L variant (also known as c.190T>C), located in coding exon 2 of the TTR gene, results from a T to C substitution at nucleotide position 190. The phenylalanine at codon 64 is replaced by leucine, an amino acid with highly similar properties. This variant (also described as p.F44L) has been reported in an individual with amyloidosis, who also had an additional TTR variant detected (Connors LH et al. Am. Heart J., 2009 Oct;158:607-14). This variant was also reported in one individual from a hypertrophic cardiomyopathy (HCM) cohort; however, clinical details were limited (Walsh R et al. Genet. Med., 2017 02;19:192-203). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (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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A multicentric study of the disease risks and first manifestations in hereditary transthyretin amyloidosis (ATTRv): insights for an earlier diagnosis. | Planté-Bordeneuve V | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 2023 | PMID: 36994840 |
Hereditary Transthyretin-Related Amyloidosis: Genetic Heterogeneity and Early Personalized Gene Therapy. | Dugo K | Biomedicines | 2022 | PMID: 36289657 |
Kidney involvement in hereditary transthyretin amyloidosis: a cohort study of 103 patients. | Solignac J | Clinical kidney journal | 2022 | PMID: 36003663 |
A natural history analysis of asymptomatic TTR gene carriers as they develop symptomatic transthyretin amyloidosis in the Transthyretin Amyloidosis Outcomes Survey (THAOS). | Coelho T | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 2022 | PMID: 35730447 |
ATTRv amyloidosis Italian Registry: clinical and epidemiological data. | Russo M | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 2020 | PMID: 32696671 |
Low Sensitivity of Bone Scintigraphy in Detecting Phe64Leu Mutation-Related Transthyretin Cardiac Amyloidosis. | Musumeci MB | JACC. Cardiovascular imaging | 2020 | PMID: 31864976 |
Sudoscan in the evaluation and follow-up of patients and carriers with TTR mutations: experience from an Italian Centre. | Luigetti M | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 2018 | PMID: 30638075 |
A new staging system for cardiac transthyretin amyloidosis. | Gillmore JD | European heart journal | 2018 | PMID: 29048471 |
Magnetic Resonance in Transthyretin Cardiac Amyloidosis. | Martinez-Naharro A | Journal of the American College of Cardiology | 2017 | PMID: 28728692 |
Genetic testing improves identification of transthyretin amyloid (ATTR) subtype in cardiac amyloidosis. | Brown EE | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 2017 | PMID: 28494620 |
Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. | Walsh R | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 27532257 |
Transthyretin-Related Familial Amyloid Polyneuropathy (TTR-FAP): A Single-Center Experience in Sicily, an Italian Endemic Area. | Mazzeo A | Journal of neuromuscular diseases | 2015 | PMID: 27858761 |
Frequencies and geographic distributions of genetic mutations in transthyretin- and non-transthyretin-related familial amyloidosis. | Zhen DB | Clinical genetics | 2015 | PMID: 25211232 |
The prognostic significance of central hemodynamics in patients with cardiac amyloidosis. | Russo C | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 2013 | PMID: 23885891 |
Presence of N-glycosylated transthyretin in plasma of V30M carriers in familial amyloidotic polyneuropathy: an escape from ERAD. | Teixeira AC | Journal of cellular and molecular medicine | 2013 | PMID: 23387326 |
THAOS - The Transthyretin Amyloidosis Outcomes Survey: initial report on clinical manifestations in patients with hereditary and wild-type transthyretin amyloidosis. | Coelho T | Current medical research and opinion | 2013 | PMID: 23193944 |
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 |
Seeking confidence in the diagnosis of systemic AL (Ig light-chain) amyloidosis: patients can have both monoclonal gammopathies and hereditary amyloid proteins. | Comenzo RL | Blood | 2006 | PMID: 16439680 |
Genetic study of transthyretin amyloid neuropathies: carrier risks among French and Portuguese families. | Planté-Bordeneuve V | Journal of medical genetics | 2003 | PMID: 14627687 |
Transthyretin amyloidosis (serine 44) with headache, hearing loss, and peripheral neuropathy. | Klein CJ | Neurology | 1998 | PMID: 9818883 |
A simple screening test for variant transthyretins associated with familial transthyretin amyloidosis using isoelectric focusing. | Connors LH | Biochimica et biophysica acta | 1998 | PMID: 9748569 |
Homozygosity and heterozygosity for the transthyretin Leu64 mutation: clinical, biochemical and molecular findings. | Ferlini A | Clinical genetics | 1996 | PMID: 8721565 |
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Text-mined citations for rs138065384 ...
HelpRecord last updated Sep 29, 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.