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:: RCV000159420.28

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:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000209366	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Pathogenic (Aug 24, 2017)	germline	clinical testing	Citation Link,
SCV002048940	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021)	Pathogenic (Feb 24, 2021)	germline	clinical testing	Citation Link,
SCV002563459	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Dec 1, 2021)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000209366

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Pathogenic
(Aug 24, 2017)

germline

clinical testing

Citation Link,

SCV002048940

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process 2021)

Pathogenic
(Feb 24, 2021)

germline

clinical testing

Citation Link,

SCV002563459

CeGaT Center for Human Genetics Tuebingen

criteria provided, single submitter

(CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)

Pathogenic
(Dec 1, 2021)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Details of each submission

From GeneDx, SCV000209366.13

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not 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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

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

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV002563459.14

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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