NM_000371.4(TTR):c.140A>G (p.Asn47Ser) AND Amyloidosis, hereditary systemic 1

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jan 16, 2024
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:: RCV000228167.8

Allele description [Variation Report for NM_000371.4(TTR):c.140A>G (p.Asn47Ser)]

NM_000371.4(TTR):c.140A>G (p.Asn47Ser)

Gene:

TTR:transthyretin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

18q12.1

Genomic location:

Preferred name:

NM_000371.4(TTR):c.140A>G (p.Asn47Ser)

Other names:

p.N47S:AAT>AGT

HGVS:

NC_000018.10:g.31592966A>G
NG_009490.1:g.6200A>G
NM_000371.4:c.140A>GMANE SELECT
NP_000362.1:p.Asn47Ser
NP_000362.1:p.Asn47Ser
LRG_416t1:c.140A>G
LRG_416:g.6200A>G
LRG_416p1:p.Asn47Ser
NC_000018.9:g.29172929A>G
NM_000371.3:c.140A>G

Protein change:

N47S

Links:

dbSNP: rs145551875

NCBI 1000 Genomes Browser:

rs145551875

Molecular consequence:

NM_000371.4:c.140A>G - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000284747	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 16, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 32746448, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000284747

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 16, 2024)

germline

clinical testing

PubMed (2)
[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 variant burden and adverse outcomes in pediatric cardiomyopathy.

Burstein DS, Gaynor JW, Griffis H, Ritter A, Connor MJO, Rossano JW, Lin KY, Ahrens-Nicklas RC.

Pediatr Res. 2021 May;89(6):1470-1476. doi: 10.1038/s41390-020-1101-5. Epub 2020 Aug 3.

PubMed [citation]

PMID:: 32746448
PMCID:: PMC8256333

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000284747.8

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

Description

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 47 of the TTR protein (p.Asn47Ser). This variant is present in population databases (rs145551875, gnomAD 0.02%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 32746448). ClinVar contains an entry for this variant (Variation ID: 178279). 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 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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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