ClinVar Genomic variation as it relates to human health
NM_000371.4(TTR):c.95T>C (p.Leu32Pro)
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.95T>C (p.Leu32Pro)
Variation ID: 13457 Accession: VCV000013457.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q12.1 18: 31592921 (GRCh38) [ NCBI UCSC ] 18: 29172884 (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 Aug 29, 2016 Apr 6, 2024 Jun 23, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000371.4:c.95T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000362.1:p.Leu32Pro missense NC_000018.10:g.31592921T>C NC_000018.9:g.29172884T>C NG_009490.1:g.6155T>C LRG_416:g.6155T>C P02766:p.Leu32Pro - Protein change
- L32P
- Other names
- L12P
- Canonical SPDI
- NC_000018.10:31592920: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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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 (2) |
criteria provided, single submitter
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Jun 23, 2023 | RCV000014399.26 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 5, 2019 | RCV001001339.8 |
Submissions - Germline
Classification
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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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Pathogenic
(Jun 23, 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: SCV004297823.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TTR function (PMID: 15820680). Advanced modeling … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TTR function (PMID: 15820680). 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. ClinVar contains an entry for this variant (Variation ID: 13457). This variant is also known as Leu12Pro. This missense change has been observed in individual(s) with TTR-related conditions (PMID: 10071047, 20209591). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 32 of the TTR protein (p.Leu32Pro). (less)
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Pathogenic
(Jun 05, 2019)
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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: SCV001158531.1
First in ClinVar: Feb 10, 2020 Last updated: Feb 10, 2020 |
Comment:
The TTR c.95T>C; p.Leu32Pro variant (rs121918094), also known as p.Leu12Pro in alternative nomenclature, is reported in the literature in multiple individuals affected with TTR amyloidosis, … (more)
The TTR c.95T>C; p.Leu32Pro variant (rs121918094), also known as p.Leu12Pro in alternative nomenclature, is reported in the literature in multiple individuals affected with TTR amyloidosis, including several individuals presenting with leptomeningeal amyloidosis (Brett 1999, McColgan 2015) and two siblings presenting with seizures and hypertrophic heart disease (Barreiros 2010). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The leucine at codon 32 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Consistent with these predictions, functional studies indicate that variant protein forms aggregates in cultured cells and mouse hepatocytes (Batista 2013) and exhibits altered multimerization properties compared to wildtype protein (Altland 2007). 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. Barreiros AP et al. Liver transplantation and combined liver-heart transplantation in patients with familial amyloid polyneuropathy: a single-center experience. Liver Transpl. 2010 Mar;16(3):314-23. Batista AR et al. Hepatic production of transthyretin L12P leads to intracellular lysosomal aggregates in a new somatic transgenic mouse model. Biochim Biophys Acta. 2013 Aug;1832(8):1183-93. Brett M et al. Transthyretin Leu12Pro is associated with systemic, neuropathic and leptomeningeal amyloidosis. Brain. 1999 Feb;122 ( Pt 2):183-90. McColgan P et al. Oculoleptomeningeal Amyloidosis associated with transthyretin Leu12Pro in an African patient. J Neurol. 2015 Jan;262(1):228-34. (less)
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Pathogenic
(Apr 03, 2024)
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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: SCV000034648.3
First in ClinVar: Apr 04, 2013 Last updated: Apr 06, 2024 |
Comment on evidence:
Brett et al. (1999) described the case of a middle-aged woman with a leu12-to-pro (L12P) mutation of the TTR gene product, an extensive amyloid deposition … (more)
Brett et al. (1999) described the case of a middle-aged woman with a leu12-to-pro (L12P) mutation of the TTR gene product, an extensive amyloid deposition in the leptomeninges and liver as well as the involvement of the heart and peripheral nervous system, typical of familial amyloid polyneuropathy caused by variant TTR (105210). Clinical features attributed to her leptomeningeal amyloid included radiculopathy, central hypoventilation, recurrent subarachnoid hemorrhage, depression, seizures, and periods of decreased consciousness. MRI showed a marked enhancement throughout her meninges and ependyma, and TTR amyloid deposition was confirmed by meningeal biopsy. The simultaneous presence of extensive visceral amyloid and clinically significant deposits affecting both peripheral and central nervous system extended the spectrum of amyloid-related disease associated with TTR mutations. Brett et al. (1999) suggested that leptomeningeal amyloidosis should be considered part of the syndrome of TTR-related familial amyloid polyneuropathy. Their index case was 38 years old when she first began to notice easy bruising. Five years later she began to get persistent headaches, and 6 months later presented with severe headache of sudden onset. CT and lumbar puncture confirmed subarachnoid blood, but angiograms showed no definite bleeding point. Two months later she had another subarachnoid bleed. About 4 years later, she started to notice hearing loss bilaterally, increasingly severe headaches, unsteadiness, urinary frequency, incomplete bladder emptying, and poor urinary stream. A CT scan showed hydrocephalus; insertion of a right lateral ventriculoperitoneal shunt was complicated by a small subdural hematoma. After the shunt, her unsteadiness and urinary symptoms partially improved. After a complicated and distressing course the patient died at the age of 53 years. The family history showed that the mother had committed suicide at the age of 62 after 2 years of depression and physical illness that included urinary symptoms, constipation, and falls. However, histologic study of sections of heart, lung, and kidney from the mother's postmortem material showed no amyloid. (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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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 |
The biological and chemical basis for tissue-selective amyloid disease. | Sekijima Y | Cell | 2005 | PMID: 15820680 |
Transthyretin Leu12Pro is associated with systemic, neuropathic and leptomeningeal amyloidosis. | Brett M | Brain : a journal of neurology | 1999 | PMID: 10071047 |
Brett, M., Persey, M. R., Reilly, M. M., Revesz, T., Booth, D. R., Booth, S. E., Hawkins, P. N., Pepys, M. B., Morgan-Hughes, J. A. Transthyretin leu12pro is associated with systemic, neuropathic and leptomeningeal amyloidosis. Brain 122: 183-190, 1999. | - | - | - | - |
Text-mined citations for rs121918094 ...
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.