ClinVar Genomic variation as it relates to human health
NM_000371.4(TTR):c.391C>A (p.Leu131Met)
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.391C>A (p.Leu131Met)
Variation ID: 13424 Accession: VCV000013424.2
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q12.1 18: 31598622 (GRCh38) [ NCBI UCSC ] 18: 29178585 (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 Jun 18, 2018 Apr 15, 2023 Jan 30, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000371.4:c.391C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000362.1:p.Leu131Met missense NM_000371.3:c.391C>A NC_000018.10:g.31598622C>A NC_000018.9:g.29178585C>A NG_009490.1:g.11856C>A LRG_416:g.11856C>A LRG_416t1:c.391C>A P02766:p.Leu131Met - Protein change
- L131M
- Other names
- L111M
- Canonical SPDI
- NC_000018.10:31598621:C: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.
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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 | 416 |
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 (1) |
no assertion criteria provided
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Oct 1, 1993 | RCV000014366.27 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 30, 2023 | RCV003162251.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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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
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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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Likely pathogenic
(Jan 30, 2023)
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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: SCV003904897.1
First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023 |
Comment:
The p.L131M variant (also known as c.391C>A), located in coding exon 4 of the TTR gene, results from a C to A substitution at nucleotide … (more)
The p.L131M variant (also known as c.391C>A), located in coding exon 4 of the TTR gene, results from a C to A substitution at nucleotide position 391. The leucine at codon 131 is replaced by methionine, an amino acid with highly similar properties. This alteration, which is also reported as p.L111M, has been detected in several individuals with transthyretin (TTR) amyloidosis and related cardiomyopathy and TTR amyloidosis cohorts (Nordlie M et al. Scand J Immunol, 1988 Jan;27:119-22; Altland K et al. Electrophoresis, 2007 Jun;28:2053-64; Nelson LM et al. Clin Transplant, 2013 Dec;27:203-9; Suhr OB et al. Transplantation, 2016 Feb;100:373-81; Damy T et al. Eur Heart J, 2019 Apr;43:391-400; Caponetti AG et al. JACC Heart Fail, 2021 Oct;9:736-746; Barroso FA et al. Amyloid, 2022 Sep;29:175-183; Dispenzieri A et al. Orphanet J Rare Dis, 2022 Jun;17:236). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 majority of available evidence to date, this variant is likely to be pathogenic. (less)
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Pathogenic
(Oct 01, 1993)
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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: SCV000034615.4
First in ClinVar: Apr 04, 2013 Last updated: Jun 18, 2018 |
Comment on evidence:
Frederiksen et al. (1962) in Denmark described a family in which 7 of 12 sibs had progressive heart failure due to cardiac amyloidosis (105210). The … (more)
Frederiksen et al. (1962) in Denmark described a family in which 7 of 12 sibs had progressive heart failure due to cardiac amyloidosis (105210). The onset of heart failure was at about age 40 years, with progression to death in 3 to 6 years. Cardiac catheterization showed constrictive-type right-ventricular pressure curves. The children and grandchildren of the affected persons were too young to show the condition. The father was living and well at age 74. The mother, who died in the influenza epidemic of 1918, was said to have been always sickly and to have swollen legs, but did bear 12 offspring. Husby et al. (1986) found a substitution of methionine for leucine at position 111 in transthyretin (L111M) as the basis of the cardiac amyloidosis described in Danes by Frederiksen et al. (1962). Nordvag et al. (1992) described a diagnostic test for the molecular detection of this mutation. DdeI digestion of PCR-amplified genomic DNA from patients revealed 3 bands by gel electrophoresis, whereas amplified DNA of controls showed 2 bands. Nordvag et al. (1993) applied this test in a retrospective study of DNA from 65 formalin-fixed, paraffin-embedded tissues obtained at autopsy or biopsy from 29 members of the Danish family. The leu111-to-met mutation was found in 10, whereas 13 were not affected. The results were consistent with known clinical data and with corresponding serum TTR examinations. Ranlov et al. (1992) gave a follow-up on the original Danish kindred. They had available stored, frozen serum samples obtained in 1959 and 1960 from 36 of 40 living members of the kindred. They found that none of the 18 members of the kindred who tested negative for the leu111-to-met mutation had developed cardiomyopathy. The leu111-to-met carrier who died as a result of an accident at age 22 showed no postmortem evidence of amyloid deposits. All 7 persons who developed amyloidosis had the mutation. In an accompanying editorial, Benson (1992) pointed out features of amyloid cardiomyopathy that should be considered when there are systemic features such as nephrotic syndrome, gastrointestinal motility disturbance, neuropathy, and purpura. Cardiac amyloidosis can result in angina pectoris when there is no significant coronary vessel disease, possibly because of small vessel rigidity due to amyloid deposits. The typical electrocardiogram shows changes usually interpreted as 'anteroseptal myocardial infarction, age undetermined.' The 'pseudoinfarction' pattern results presumably from dense amyloid infiltration. Left atrial enlargement results from the restrictive nature of the process. The echocardiogram may be interpreted as showing 'good systolic function'; the pathophysiologic problem is in filling, not emptying, of the ventricle. Nordvag (1995) indicated that carpal tunnel syndrome was the presenting symptom in the Danish kindred with familial amyloid cardiopathy, although the heart was the major affected organ. Patients with the leu111-to-met mutation had significantly depressed free thyroxine serum levels. Benson (2001) noted that the kindred originally described by Frederiksen et al. (1962) was the only one to be reported with this mutation. This form of amyloidosis had been referred to as the Danish or cardiac type. (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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Clinical and genetic profile of patients enrolled in the Transthyretin Amyloidosis Outcomes Survey (THAOS): 14-year update. | Dispenzieri A | Orphanet journal of rare diseases | 2022 | PMID: 35717381 |
Characteristics of patients with autonomic dysfunction in the Transthyretin Amyloidosis Outcomes Survey (THAOS). | Barroso FA | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 2022 | PMID: 35451899 |
Transthyretin cardiac amyloidosis in continental Western Europe: an insight through the Transthyretin Amyloidosis Outcomes Survey (THAOS). | Damy T | European heart journal | 2022 | PMID: 30938420 |
Sex-Related Risk of Cardiac Involvement in Hereditary Transthyretin Amyloidosis: Insights From THAOS. | Caponetti AG | JACC. Heart failure | 2021 | PMID: 34391735 |
Survival After Transplantation in Patients With Mutations Other Than Val30Met: Extracts From the FAP World Transplant Registry. | Suhr OB | Transplantation | 2016 | PMID: 26656838 |
Outcome in patients treated with isolated liver transplantation for familial transthyretin amyloidosis to prevent cardiomyopathy. | Nelson LM | Clinical transplantation | 2015 | PMID: 26361241 |
Long-term outcome in patients treated with combined heart and liver transplantation for familial amyloidotic cardiomyopathy. | Nelson LM | Clinical transplantation | 2013 | PMID: 23278526 |
Genetic microheterogeneity of human transthyretin detected by IEF. | Altland K | Electrophoresis | 2007 | PMID: 17503405 |
Retrospective molecular detection of Transthyretin Met 111 mutation in a Danish kindred with familial amyloid cardiomyopathy, using DNA from formalin-fixed and paraffin-embedded tissues. | Nordvåg BY | Human genetics | 1993 | PMID: 8406434 |
A transthyretin variant (alanine 71) associated with familial amyloidotic polyneuropathy in a French family. | Benson MD 2nd | Journal of medical genetics | 1993 | PMID: 8095302 |
A Danish kindred with familial amyloid cardiomyopathy revisited: identification of a mutant transthyretin-methionine111 variant in serum from patients and carriers. | Ranløv I | The American journal of medicine | 1992 | PMID: 1626570 |
Molecular diagnosis of the transthyretin (TTR) Met111 mutation in familial amyloid cardiomyopathy of Danish origin. | Nordvåg BY | Human genetics | 1992 | PMID: 1618497 |
A new prealbumin variant in familial amyloid cardiomyopathy of Danish origin. | Nordlie M | Scandinavian journal of immunology | 1988 | PMID: 3340821 |
Familial primary amyloidosis with severe amyloid heart disease. | FREDERIKSEN T | The American journal of medicine | 1962 | PMID: 13894830 |
Benson, M. D. Characterization of an amyloid fibril protein in heredofamilial amyloidosis. (Abstract) Clin. Res. 28: 340A, 1980. | - | - | - | - |
Husby, G., Ranlov, P. J., Sletten, K., Marhaug, G. Prealbumin nature of the amyloid in familial amyloid cardiomyopathy of Danish origin. In: Glenner, G. G., Osserman, E. F., Bendit, E. P., Calkins, E., Cohen, A. S., Zucker-Franklin, D. (eds.) Amyloidosis. New York: Plenum (pub.) 391-399, 1986. | - | - | - | - |
Nordvag, B.-Y. Molecular genetic studies of inherited, transthyretin-related amyloidosis causing severe cardiac disease in a Danish family. (Abstract) Scand. J. Rheum. 24: 179, 1995. | - | - | - | - |
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Text-mined citations for rs121918073 ...
HelpRecord last updated Mar 23, 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.