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NM_000371.4(TTR):c.118G>A (p.Val40Ile) AND not provided

Germline classification:
Pathogenic (3 submissions)
Last evaluated:
Dec 1, 2021
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000159420.30

Allele description [Variation Report for NM_000371.4(TTR):c.118G>A (p.Val40Ile)]

NM_000371.4(TTR):c.118G>A (p.Val40Ile)

Gene:
TTR:transthyretin [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
18q12.1
Genomic location:
Preferred name:
NM_000371.4(TTR):c.118G>A (p.Val40Ile)
Other names:
V20I; p.V40I:GTC>ATC
HGVS:
  • NC_000018.10:g.31592944G>A
  • NG_009490.1:g.6178G>A
  • NM_000371.4:c.118G>AMANE SELECT
  • NP_000362.1:p.Val40Ile
  • NP_000362.1:p.Val40Ile
  • LRG_416t1:c.118G>A
  • LRG_416:g.6178G>A
  • LRG_416p1:p.Val40Ile
  • NC_000018.9:g.29172907G>A
  • NM_000371.3:c.118G>A
  • P02766:p.Val40Ile
Protein change:
V40I; VAL20ILE
Links:
UniProtKB: P02766#VAR_007550; OMIM: 176300.0039; dbSNP: rs121918093
NCBI 1000 Genomes Browser:
rs121918093
Molecular consequence:
  • NM_000371.4:c.118G>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Synonyms:
none provided
Identifiers:
MedGen: C3661900

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000209366GeneDx
criteria provided, single submitter

(GeneDx Variant Classification (06012015))
Pathogenic
(Aug 24, 2017)
germlineclinical testing

Citation Link,

SCV002048940ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process 2021)
Pathogenic
(Feb 24, 2021)
germlineclinical testing

Citation Link,

SCV002563459CeGaT Center for Human Genetics Tuebingen
criteria provided, single submitter

(CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)
Pathogenic
(Dec 1, 2021)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes1not providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Details of each submission

From GeneDx, SCV000209366.13

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

This variant is denoted p.Val40Ile (V40I) GTC>ATC: c.118 G>A in exon 2 of the TTR gene (NM_000371.3). The Val40Ile variant (also known as Val20Ile, due to a difference in cDNA numbering) in the TTR gene, has been published in association with cardiac amyloidosis (Jenne D et al., 1996; Barreiros A et al., 2010). Jenne et al. (1996) reported the Val40Ile mutation in a German family with severe amyloid cardiomyopathy. The same study demonstrated that Val40Ile causes significant loss of tetramer stability. Barreiros et al. (2010) reported Val40Ile in a 56 year old patient with sensory-motor polyneuropathy and restrictive cardiomyopathy. Mutations in nearby codons (Asp38Asn, Asp38Gly, Asp38Glu, Ser43Asn) have also been reported in association with amyloidosis, further supporting the functional importance of this region of the protein. Furthermore, Val40Ile was not detected in up to 400 control alleles from Caucasian and African American individuals tested at GeneDx, indicating it is not a common benign polymorphism in these populations. The variant is found in TTR panel(s).

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

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV002048940.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The TTR c.118G>A; p.Val40Ile variant (rs121918093), also known as p.Val20Ile, is reported in the literature in multiple individuals and one family affected with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (Auer-Grumbach 2020, Bauer 2014, Jenne 1996). Functional analyses of the variant protein show significantly reduced tetramer stability (Jenne 1996, Atland 2007, Sekijima 2005). This variant is also reported in ClinVar (Variation ID: 13455). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The valine at codon 40 is highly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.697). 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. Auer-Grumbach M et al. Hereditary ATTR Amyloidosis in Austria: Prevalence and Epidemiological Hot Spots. J Clin Med. 2020 Jul 14;9(7):2234. Bauer R et al. The "Wagshurst study": p.Val40Ile transthyretin gene variant causes late-onset cardiomyopathy. Amyloid. 2014 Dec;21(4):267-75. Jenne DE et al. A new isoleucine substitution of Val-20 in transthyretin tetramers selectively impairs dimer-dimer contacts and causes systemic amyloidosis. Proc Natl Acad Sci U S A. 1996 Jun 25;93(13):6302-7. Sekijima Y et al. The biological and chemical basis for tissue-selective amyloid disease. Cell. 2005 Apr 8;121(1):73-85.

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

From CeGaT Center for Human Genetics Tuebingen, SCV002563459.16

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided1not providednot providednot provided

Last Updated: Nov 3, 2024