ClinVar Genomic variation as it relates to human health
NM_000371.4(TTR):c.233T>A (p.Leu78His)
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.233T>A (p.Leu78His)
Variation ID: 13420 Accession: VCV000013420.27
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q12.1 18: 29175115 (GRCh37) [ NCBI UCSC ] 18: 31595152 (GRCh38) [ 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 May 1, 2024 Jan 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000371.4:c.233T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000362.1:p.Leu78His missense NC_000018.10:g.31595152T>A NC_000018.9:g.29175115T>A NG_009490.1:g.8386T>A LRG_416:g.8386T>A LRG_416t1:c.233T>A LRG_416p1:p.Leu78His P02766:p.Leu78His - Protein change
- L78H
- Other names
- L58H
- p.L78H:CTC>CAC
- Canonical SPDI
- NC_000018.10:31595151:T: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
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00002
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
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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 |
371 | 415 |
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. |
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Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jan 31, 2024 | RCV000014362.38 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Aug 18, 2023 | RCV000159437.19 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 24, 2021 | RCV002444430.3 |
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
(Jul 25, 2016)
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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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Athena Diagnostics Inc
Accession: SCV000616212.1
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
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Pathogenic
(Nov 10, 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: SCV000696619.1
First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017 |
Comment:
Variant summary: The TTR c.233T>A (p.Leu78His) variant indicated to be located in the loop region (Cendron_2009) causes a missense change involving a conserved nucleotide with … (more)
Variant summary: The TTR c.233T>A (p.Leu78His) variant indicated to be located in the loop region (Cendron_2009) causes a missense change involving a conserved nucleotide with 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a damaging outcome for this variant. In addition, mutations in this residue (L78R) and in nearby residues (H76R, G77R, T79R, T79K) have been reported in association with amyloidosis, further supporting the functional importance of this region of the protein. The variant of interest was not observed in controls (ExAC, 1000 Gs, or ESP) and is a common TTR disease variant that is reported to be detected in >50 published cases, usually presenting with carpal tunnel syndrome and slowly progressing over two decades (Miller_2004). Multiple clinical diagnostic laboratories/databases cite the variant as "pathogenic." Therefore, the variant of interest has been classified as Pathogenic. (less)
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Likely pathogenic
(May 31, 2022)
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criteria provided, single submitter
Method: clinical testing
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Familial amyloid neuropathy
Affected status: yes
Allele origin:
paternal
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV002526732.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
Comment:
_x000D_ Criteria applied: PS3, PM2_SUP, PM1_SUP, PM5, PS4_MOD
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Pathogenic
(Aug 18, 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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GeneDx
Accession: SCV000209383.14
First in ClinVar: Feb 24, 2015 Last updated: Aug 31, 2023 |
Comment:
Identified in association with amyloidosis and amyloidotic polyneuropathy (Nichols et al., 1989; Barreiros et al., 2010; Suhr et al., 2016; Tebbe et al., 2016; Skrahina … (more)
Identified in association with amyloidosis and amyloidotic polyneuropathy (Nichols et al., 1989; Barreiros et al., 2010; Suhr et al., 2016; Tebbe et al., 2016; Skrahina et al., 2021; Trachtenberg et al., 2021; Ungerer et al., 2021); also reported as L58H due to alternative nomenclature; Functional studies have shown that L78H, located in the loop region, results in a small but significant conformational change that affects the stability of the protein tetramer (Sekijima et al., 2005; Atland et al., 2007; Cendron et al., 2009); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 1644839, 17503405, 19602727, 22620962, 25526974, 2613237, 27724962, 17143887, 1656975, 25604431, 26656838, 20209591, 15820680, 34461735, 34658264, 33283548, 37014422) (less)
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Pathogenic
(Jan 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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Familial amyloid neuropathy
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000648564.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with histidine, which is basic and polar, at codon 78 of the TTR protein (p.Leu78His). … (more)
This sequence change replaces leucine, which is neutral and non-polar, with histidine, which is basic and polar, at codon 78 of the TTR protein (p.Leu78His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (PMID: 2613237, 9196903, 17503405, 20209591, 25526974, 27724962). This variant is also known as p.Leu58His. ClinVar contains an entry for this variant (Variation ID: 13420). 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: 15820680, 19602727). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jun 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: SCV001746314.14
First in ClinVar: Jul 10, 2021 Last updated: Apr 15, 2024 |
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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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002732384.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.L78H variant (also known as c.233T>A and L58H), located in coding exon 3 of the TTR gene, results from a T to A substitution … (more)
The p.L78H variant (also known as c.233T>A and L58H), located in coding exon 3 of the TTR gene, results from a T to A substitution at nucleotide position 233. The leucine at codon 78 is replaced by histidine, an amino acid with similar properties. This alteration has been seen in multiple individuals with familial transthyretin amyloidosis whose symptoms generally included carpal tunnel syndrome, generalized neuropathy, amyloid deposits and positive congo red staining (Nichols WC, et al. Genomics 1989;5(3):535-40; Barreiros AP, et al. Liver Transpl. 2010;16(3):314-23; Connors LH, et al. Biochim. Biophys. Acta 1998;1407(3):185-92; Ungerer MN et al. Amyloid, 2020 Dec;:1-9). In two additional studies, a small difference in the crystal structure of this variant compared with wild type was noted and the variant was shown to unfold 90% at 2.5M urea, indicating decreased conformation stability in the folded state (Altland K, et al. Electrophoresis 2007;28(12):2053-64; Cendron L, et al. J. Biol. Chem. 2009 Sep; 284(38):25832-41). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Zhang J et al. Environ Sci Technol, 2018 10;52:11865-11874). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Feb 27, 2001)
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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: SCV000034611.4
First in ClinVar: Apr 04, 2013 Last updated: Jun 18, 2018 |
Comment on evidence:
Substitution of histidine for leucine at position 58 (A-to-T change) of the TTR gene (L58H) results in the amyloid polyneuropathy (105210) observed in the large … (more)
Substitution of histidine for leucine at position 58 (A-to-T change) of the TTR gene (L58H) results in the amyloid polyneuropathy (105210) observed in the large Maryland kindred of German extraction studied by Mahloudji et al. (1969) and thought by them on clinical grounds alone to have the same disorder as that reported by Rukavina et al. (1956); see 176300.0006. This was the first amyloidosis-producing mutation in TTR to be identified by direct sequencing after amplification of the gene by PCR. Nichols et al. (1989) demonstrated a T-to-A substitution at the second base of the codon for leucine 58 causing a change to histidine. Since the mutation did not result in a change in the restriction pattern of the prealbumin gene, Nichols et al. (1989) developed a new method for direct detection of single-base changes in genomic DNA using PCR and an allele-specific oligonucleotide primer. Mendell et al. (1990) diagnosed the defect in the Maryland/German type by allele-specific enzymatic amplification of genomic DNA to demonstrate the his58 mutation. Hund et al. (2001) noted that the Maryland/German type of familial amyloid polyneuropathy (described by Mahloudji et al. (1969) and resulting from a L58H substitution) had been classified as familial amyloid polyneuropathy type II (FAP II). FAP II is characterized by a course of disease with polyneuropathy beginning at the hands and frequent carpal tunnel syndrome operations. Benson (2001) noted that in FAP resulting from the L58H mutation, death is frequently caused by cardiomyopathy. The Maryland/German type is distinguished from the Indiana/Swiss type (176300.0006) by a lack of vitreous opacities. Although they also lived in the Maryland area, the family originally reported by Shulman and Bartter (1956), Kaufman (1958), Kaufman and Thomas (1959), Wong and McFarlin (1967), and Dalakas and Engel (1981) was thought to have had a different mutation (Jacobson et al., 1987; Buxbaum, 1987). The disorder in this kindred was unusually severe with relatively early death and extensive involvement of the ocular vitreous. Jacobson et al. (1992) indeed demonstrated a distinct mutation: a leu55-to-pro substitution in the TTR gene (176300.0022). (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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Real-world outcomes in non-endemic hereditary transthyretin amyloidosis with polyneuropathy: a 20-year German single-referral centre experience. | Ungerer MN | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 2021 | PMID: 33283548 |
Interspecies Variation between Fish and Human Transthyretins in Their Binding of Thyroid-Disrupting Chemicals. | Zhang J | Environmental science & technology | 2018 | PMID: 30226982 |
Endomyocardial biopsy in patients with cardiomyopathy of unknown origin: does specialized center experience apply to a tertiary care hospital? | Tebbe U | BMC research notes | 2016 | PMID: 27724962 |
Survival After Transplantation in Patients With Mutations Other Than Val30Met: Extracts From the FAP World Transplant Registry. | Suhr OB | Transplantation | 2016 | PMID: 26656838 |
Cardiac findings and events observed in an open-label clinical trial of tafamidis in patients with non-Val30Met and non-Val122Ile hereditary transthyretin amyloidosis. | Damy T | Journal of cardiovascular translational research | 2015 | PMID: 25743445 |
In vivo detection of nerve injury in familial amyloid polyneuropathy by magnetic resonance neurography. | Kollmer J | Brain : a journal of neurology | 2015 | PMID: 25526974 |
Frequencies and geographic distributions of genetic mutations in transthyretin- and non-transthyretin-related familial amyloidosis. | Zhen DB | Clinical genetics | 2015 | PMID: 25211232 |
Genotype--phenotype correlation in FAP. | Zeldenrust SR | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 2012 | PMID: 22620962 |
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: the servant of many masters. | Buxbaum JN | Cellular and molecular life sciences : CMLS | 2009 | PMID: 19644733 |
Amyloidogenic potential of transthyretin variants: insights from structural and computational analyses. | Cendron L | The Journal of biological chemistry | 2009 | PMID: 19602727 |
Genetic microheterogeneity of human transthyretin detected by IEF. | Altland K | Electrophoresis | 2007 | PMID: 17503405 |
Destabilization of transthyretin by pathogenic mutations in the DE loop. | Takeuchi M | Proteins | 2007 | PMID: 17143887 |
The biological and chemical basis for tissue-selective amyloid disease. | Sekijima Y | Cell | 2005 | PMID: 15820680 |
Identification of transthyretin variants by sequential proteomic and genomic analysis. | Bergen HR 3rd | Clinical chemistry | 2004 | PMID: 15217993 |
Native state stabilization by NSAIDs inhibits transthyretin amyloidogenesis from the most common familial disease variants. | Miller SR | Laboratory investigation; a journal of technical methods and pathology | 2004 | PMID: 14968122 |
Transthyretin-associated neuropathic amyloidosis. Pathogenesis and treatment. | Hund E | Neurology | 2001 | PMID: 11261421 |
A simple screening test for variant transthyretins associated with familial transthyretin amyloidosis using isoelectric focusing. | Connors LH | Biochimica et biophysica acta | 1998 | PMID: 9748569 |
A European family with histidine 58 transthyretin mutation in familial amyloid polyneuropathy. | Goebel HH | Neuromuscular disorders : NMD | 1997 | PMID: 9196903 |
Transthyretin ILE20, a new variant associated with late-onset cardiac amyloidosis. | Jacobson DR | Human mutation | 1997 | PMID: 8990019 |
A specific test for transthyretin 122 (Val----Ile), based on PCR-primer-introduced restriction analysis (PCR-PIRA): confirmation of the gene frequency in blacks. | Jacobson DR | American journal of human genetics | 1992 | PMID: 1729888 |
Diagnosis of Maryland/German familial amyloidotic polyneuropathy using allele-specific, enzymatically amplified, genomic DNA. | Mendell JR | Annals of neurology | 1990 | PMID: 2360796 |
Direct sequencing of the gene for Maryland/German familial amyloidotic polyneuropathy type II and genotyping by allele-specific enzymatic amplification. | Nichols WC | Genomics | 1989 | PMID: 2613237 |
Amyloid in hereditary amyloid polyneuropathy is related to prealbumin. | Dalakas MC | Archives of neurology | 1981 | PMID: 7018469 |
The genetic amyloidoses with particular reference to hereditary neuropathic amyloidosis, type II (Indiana or Rukavina type). | Mahloudji M | Medicine | 1969 | PMID: 4884226 |
Primary familial amyloidosis. | Wong VG | Archives of ophthalmology (Chicago, Ill. : 1960) | 1967 | PMID: 4952599 |
Vitreous opacities diagnostic of familial primary amyloidosis. | KAUFMAN HE | The New England journal of medicine | 1959 | PMID: 14404854 |
Primary familial amyloidosis. | KAUFMAN HE | A.M.A. archives of ophthalmology | 1958 | PMID: 13593935 |
Familial primary systemic amyloidosis: an experimental, genetic and clinical study. | BLOCK WD | The Journal of investigative dermatology | 1956 | PMID: 13367520 |
Benson, M. D. Characterization of an amyloid fibril protein in heredofamilial amyloidosis. (Abstract) Clin. Res. 28: 340A, 1980. | - | - | - | - |
Nichols, W. C., Liepnieks, J. J., McKusick, V. A., Benson, M. D. A prealbumin (transthyretin) mutation associated with familial amyloidotic polyneuropathy type II (Maryland/German). (Abstract) Clin. Res. 37: 542A, 1989. | - | - | - | - |
Shulman, L. E., Bartter, F. C. Familial primary amyloidosis. (Abstract) Bull. Johns Hopkins Hosp. 98: 238-239, 1956. | - | - | - | - |
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Text-mined citations for rs121918069 ...
HelpRecord last updated May 01, 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.