NM_000371.4(TTR):c.194C>A (p.Ala65Asp) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: May 30, 2017
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:: RCV000159436.3

Allele description [Variation Report for NM_000371.4(TTR):c.194C>A (p.Ala65Asp)]

NM_000371.4(TTR):c.194C>A (p.Ala65Asp)

Gene:

TTR:transthyretin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

18q12.1

Genomic location:

Preferred name:

NM_000371.4(TTR):c.194C>A (p.Ala65Asp)

Other names:

p.A65D:GCC>GAC

HGVS:

NC_000018.10:g.31593020C>A
NG_009490.1:g.6254C>A
NM_000371.4:c.194C>AMANE SELECT
NP_000362.1:p.Ala65Asp
NP_000362.1:p.Ala65Asp
LRG_416t1:c.194C>A
LRG_416:g.6254C>A
LRG_416p1:p.Ala65Asp
NC_000018.9:g.29172983C>A
NM_000371.3:c.194C>A
P02766:p.Ala65Asp

Protein change:

A65D

Links:

UniProtKB: P02766#VAR_007559; dbSNP: rs730881169

NCBI 1000 Genomes Browser:

rs730881169

Molecular consequence:

NM_000371.4:c.194C>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
SCV000209382	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Pathogenic (Jan 19, 2012)	germline	clinical testing	Citation Link,
SCV001450358	Clinical Genetics and Genomics, Karolinska University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 30, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000209382

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Pathogenic
(Jan 19, 2012)

germline

clinical testing

Citation Link,

SCV001450358

Clinical Genetics and Genomics, Karolinska University Hospital

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(May 30, 2017)

germline

clinical testing

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

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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From GeneDx, SCV000209382.10

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

Description

This mutation is denoted Ala65Asp (aka A65D) at the protein level and c.194 C>A at the cDNA level. A heterozygous C>A nucleotide substitution in exon 2 of the TTR gene results in the replacement of an Alanine codon (GCC) with an Aspartic acid codon (GAC) at amino acid position 65 in transthyretin. The Ala65Asp (aka Ala45Asp, using alternative nomenclature) mutation in the TTR gene has been reported previously in association with cardiac amyloidosis (Saraiva M et al., 1995). The Ala65Asp mutation results in a non-conservative amino acid substitution of a non-polar Alanine residue with a polar Aspartic acid residue. Additionally, the NHLBI ESP Exome Variant Server reports Ala65Asp was not observed in approximately 5,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Furthermore, mutations in this codon (Ala65Ser, Ala65Thr) and in nearby codons (Phe64Leu, Phe64Ser, Phe64Tyr, Gly67Ala) have been reported in association with amyloidosis, further supporting the functional importance of this region of the protein. The variant is found in HCM 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 Clinical Genetics and Genomics, Karolinska University Hospital, SCV001450358.1

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

#	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: Apr 15, 2024

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