NM_000371.4(TTR):c.148G>C (p.Val50Leu) AND Amyloidosis, hereditary systemic 1

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Sep 5, 2021
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000014382.30

Allele description [Variation Report for NM_000371.4(TTR):c.148G>C (p.Val50Leu)]

NM_000371.4(TTR):c.148G>C (p.Val50Leu)

Gene:

TTR:transthyretin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

18q12.1

Genomic location:

Preferred name:

NM_000371.4(TTR):c.148G>C (p.Val50Leu)

Other names:

V30L

HGVS:

NC_000018.10:g.31592974G>C
NG_009490.1:g.6208G>C
NM_000371.4:c.148G>CMANE SELECT
NP_000362.1:p.Val50Leu
NP_000362.1:p.Val50Leu
LRG_416t1:c.148G>C
LRG_416:g.6208G>C
LRG_416p1:p.Val50Leu
NC_000018.9:g.29172937G>C
NM_000371.3:c.148G>C
P02766:p.Val50Leu

Protein change:

V50L; VAL30LEU

Links:

UniProtKB: P02766#VAR_007553; OMIM: 176300.0024; dbSNP: rs28933979

NCBI 1000 Genomes Browser:

rs28933979

Molecular consequence:

NM_000371.4:c.148G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Amyloidosis, hereditary systemic 1 (AMYLD1)
Synonyms:: Amyloidosis Transthyretin related; Amyloid polyneuropathy transthyretin related; Transthyretin amyloidosis; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0971004; MedGen: C2751492; Orphanet: 85447; Orphanet: 85451; OMIM: 105210

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gi|71586153|gnl|dbEST|30416525|gb|D 01.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000034631	OMIM	no assertion criteria provided	Pathogenic (Dec 1, 1998)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 1520326, 9843084
SCV002127487	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 5, 2021)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 1544214, 22620962, 23523753, 23833285, 24555660, 26521788, 1520326, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000034631

OMIM

no assertion criteria provided

Pathogenic
(Dec 1, 1998)

germline

literature only

PubMed (2)
[See all records that cite these PMIDs]

SCV002127487

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 5, 2021)

germline

clinical testing

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

Help

Summary from all submissions

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

Citations

PubMed

Familial amyloid polyneuropathy related to transthyretin mutation Val30 to Leu in a Japanese family.

Utsugisawa K, Tohgi H, Nagane Y, Yamagata M, Saito K, Mihara M.

Muscle Nerve. 1998 Dec;21(12):1783-5.

PubMed [citation]

PMID:: 9843084

Familial amyloidotic polyneuropathy: a new transthyretin position 30 mutation (alanine for valine) in a family of German descent.

Jones LA, Skare JC, Cohen AS, Harding JA, Milunsky A, Skinner M.

Clin Genet. 1992 Feb;41(2):70-3.

PubMed [citation]

PMID:: 1544214

See all PubMed Citations (9)

Details of each submission

From OMIM, SCV000034631.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In a Japanese patient with familial amyloid polyneuropathy (AMYLD1; 105210), Murakami et al. (1992) used single-strand conformation polymorphism analysis and sequence analysis of PCR-amplified exons of TTR to demonstrate a val30-to-leu (V30L) mutation. The mutation created a Cfr13I site. The change is in the same codon as the val30-to-met mutation found in the Andrade or Portuguese type (176300.0001); see also the val30-to-ala mutation (176300.0014).

The pathogenic significance of the V30L mutation was confirmed by Utsugisawa et al. (1998), who demonstrated the same mutation in 3 members of a Japanese family with type I FAP. The proband was a 46-year-old woman who gradually developed sensory dullness, muscle weakness, and atrophy of the legs and the arms. The pupils were dilated and did not react to light and accommodation, but were hypersensitive to both 0.1% pilocarpine and 0.125% epinephrine. Tendon reflexes were absent or diminished in the extremities. She showed severe hypesthesia in the distal parts of the extremities, but sparing joint sensation. Orthostatic hypotension was demonstrated with no change in pulse rate on assuming the standing position. Her father died at age 53 years, having had similar symptoms.

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002127487.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Val50 amino acid residue in TTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1544214, 22620962, 23523753, 23833285, 24555660, 26521788). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 13440). This variant is also known as Val30Leu. This missense change has been observed in individual(s) with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (PMID: 1520326). This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with leucine at codon 50 of the TTR protein (p.Val50Leu). The valine residue is highly conserved and there is a small physicochemical difference between valine and leucine.

#	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

Last Updated: Sep 29, 2024

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