NM_000371.4(TTR):c.210T>A (p.Ser70Arg) AND Familial amyloid neuropathy

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 11, 2024
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:: RCV000030572.9

Allele description [Variation Report for NM_000371.4(TTR):c.210T>A (p.Ser70Arg)]

NM_000371.4(TTR):c.210T>A (p.Ser70Arg)

Gene:

TTR:transthyretin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

18q12.1

Genomic location:

Preferred name:

NM_000371.4(TTR):c.210T>A (p.Ser70Arg)

HGVS:

NC_000018.10:g.31595129T>A
NG_009490.1:g.8363T>A
NM_000371.4:c.210T>AMANE SELECT
NP_000362.1:p.Ser70Arg
NP_000362.1:p.Ser70Arg
LRG_416t1:c.210T>A
LRG_416:g.8363T>A
LRG_416p1:p.Ser70Arg
NC_000018.9:g.29175092T>A
NM_000371.3:c.210T>A
P02766:p.Ser70Arg
p.SER70ARG

Protein change:

S70R

Links:

UniProtKB: P02766#VAR_007566; dbSNP: rs121918076

NCBI 1000 Genomes Browser:

rs121918076

Molecular consequence:

NM_000371.4:c.210T>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial amyloid neuropathy
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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000053244	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jul 29, 2016)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 17503405, 15123043, 11940682, 20686303, 17577688, 16357452, 22928869, 2363717, 1335038 Citation Link,
SCV000769143	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 11, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 22745357, 22928869, 23317988, 23713495, 24053266, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000053244

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Jul 29, 2016)

germline

clinical testing

PubMed (9)
[See all records that cite these PMIDs]

Citation Link,

SCV000769143

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 11, 2024)

germline

clinical testing

PubMed (6)
[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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Genetic microheterogeneity of human transthyretin detected by IEF.

Altland K, Benson MD, Costello CE, Ferlini A, Hazenberg BP, Hund E, Kristen AV, Linke RP, Merlini G, Salvi F, Saraiva MJ, Singer R, Skinner M, Winter P.

Electrophoresis. 2007 Jun;28(12):2053-64.

PubMed [citation]

PMID:: 17503405

The hereditary amyloidoses.

Benson MD.

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

PubMed [citation]

PMID:: 15123043

See all PubMed Citations (14)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000053244.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

Variant summary: The TTR c.210T>A (p.Ser70Arg) variant involves the alteration of a non-conserved nucleotide. Ser70 is located in the Transthyretin/hydroxyisourate hydrolase, superfamily domain and p.Ser70Ile has been classified as pathogenic by our laboratory, indicateing Ser70 is critical for TTR function. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in 120430 control chromosomes. This variant has been reported in numerous ATTR patients. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

#	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 Invitae, SCV000769143.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 70 of the TTR protein (p.Ser70Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with transthyretin amyloidosis (PMID: 22745357, 22928869, 23317988, 23713495, 24053266). It is commonly reported in individuals of Mexico ancestry (PMID: 22745357, 22928869, 23317988, 23713495, 24053266). This variant is also known as in other populations (PMID: 22745357, 22928869, 23317988, 23713495, 24053266). ClinVar contains an entry for this variant (Variation ID: 36890). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.

#	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: Apr 15, 2024

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