NM_000371.3(TTR):c.379A>G (p.Ile127Val) AND Amyloidogenic transthyretin amyloidosis

Clinical significance:Pathogenic (Last evaluated: Aug 27, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
4 submissions [Details]
Record status:
current
Accession:
RCV000014392.21

Allele description [Variation Report for NM_000371.3(TTR):c.379A>G (p.Ile127Val)]

NM_000371.3(TTR):c.379A>G (p.Ile127Val)

Gene:
TTR:transthyretin [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
18q12.1
Genomic location:
Preferred name:
NM_000371.3(TTR):c.379A>G (p.Ile127Val)
Other names:
I107V
HGVS:
  • NC_000018.10:g.31598610A>G
  • NG_009490.1:g.11844A>G
  • NM_000371.3:c.379A>G
  • NP_000362.1:p.Ile127Val
  • LRG_416t1:c.379A>G
  • LRG_416:g.11844A>G
  • LRG_416p1:p.Ile127Val
  • NC_000018.9:g.29178573A>G
  • P02766:p.Ile127Val
Protein change:
I127V; ILE107VAL
Links:
UniProtKB: P02766#VAR_007592; OMIM: 176300.0034; dbSNP: rs121918089
NCBI 1000 Genomes Browser:
rs121918089
Molecular consequence:
  • NM_000371.3:c.379A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Amyloidogenic transthyretin amyloidosis
Synonyms:
Amyloidosis Transthyretin related; Amyloid polyneuropathy transthyretin related; TTR amyloid neuropathy; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0007100; MedGen: C2751492; Orphanet: 85447; Orphanet: 85451; OMIM: 105210

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000034641OMIMno assertion criteria providedPathogenic
(May 1, 1994)
germlineliterature only

PubMed (1)
[See all records that cite this PMID]

SCV000696632Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Feb 26, 2016)
germlineclinical testing

PubMed (8)
[See all records that cite these PMIDs]

LabCorp Variant Classification Summary - May 2015.docx,

Citation Link,

SCV000769146Invitaecriteria provided, single submitter
Pathogenic
(Aug 27, 2020)
germlineclinical testing

PubMed (12)
[See all records that cite these PMIDs]

SCV001140874Mendelicscriteria provided, single submitter
Pathogenic
(May 28, 2019)
unknownclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

The hereditary amyloidoses.

Benson MD.

Best Pract Res Clin Rheumatol. 2003 Dec;17(6):909-27. Review.

PubMed [citation]
PMID:
15123043

Cardiac amyloidosis in African Americans: comparison of clinical and laboratory features of transthyretin V122I amyloidosis and immunoglobulin light chain amyloidosis.

Connors LH, Prokaeva T, Lim A, Th├ęberge R, Falk RH, Doros G, Berg A, Costello CE, O'Hara C, Seldin DC, Skinner M.

Am Heart J. 2009 Oct;158(4):607-14. doi: 10.1016/j.ahj.2009.08.006.

PubMed [citation]
PMID:
19781421
See all PubMed Citations (15)

Details of each submission

From OMIM, SCV000034641.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)

Description

In 2 American patients of German descent with amyloid polyneuropathy (105210), Uemichi et al. (1994) identified heterozygosity for an ATT (isoleucine) to GTT (valine) transition in the codon corresponding to amino acid 107 of mature TTR (I107V). The mutation created a new MaeIII restriction site which could be used in diagnosis. Although clinical and family information were limited, Uemichi et al. (1994) indicated that both patients had had a diagnosis of carpal tunnel syndrome at the age of 56 and subsequently developed polyneuropathy in the legs. The father of 1 of the patients had died at the age of 60 of a similar illness, and necropsy showed amyloidosis.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000696632.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (8)

Description

Variant summary: The TTR c.379A>G variant affects a conserved nucleotide, resulting in amino acid change from Ile to Val. 3/4 in-silico tools predict this variant to be benign (SNPs&GO not captured due to low reliability index). However, functional studies indicate that TTRI107V dimers and tetramers decreased stability compared to controls. This variant is not found in 121416 control chromosomes, but has been cited in numerous ATTR patients from various ethnicities. Taken together, this is a disease variant and was classified as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV000769146.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (12)

Description

This sequence change replaces isoleucine with valine at codon 127 of the TTR protein (p.Ile127Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with amyloidosis (PMID: 9748014, 20209591, 26537620, 27025994, 27066555, 7914929, 8081397, 24101130). This variant is also known as p.Ile107Val in the literature. ClinVar contains an entry for this variant (Variation ID: 13450). This variant has been reported to affect TTR protein function (PMID: 17503405). The p.Ile127 amino acid residue in TTR has been determined to be clinically significant (PMID: 24480837, 22745357). This suggests that variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Mendelics, SCV001140874.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jul 10, 2021

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