NM_000371.4(TTR):c.140A>G (p.Asn47Ser) AND not specified

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Aug 21, 2018
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:: RCV000155020.14

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]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000204703	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Jan 17, 2014)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001157822	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Uncertain significance (Aug 21, 2018)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000204703

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(Jan 17, 2014)

germline

clinical testing

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

SCV001157822

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process)

Uncertain significance
(Aug 21, 2018)

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	not provided	2	1	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000204703.5

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

Description

The Asn47Ser variant in TTR has been not been previously reported in any other f amilies with cardiomyopathy, but has been identified in 2/4406 African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/ EVS/; dbSNP rs145551875). Asparagine (Asn) at position 47 is not conserved in ev olution with one primate (bushbaby) carrying a serine (Ser; this variant) at thi s position. This raises the possibility that this change may be tolerated. Addit ional computational analyses (biochemical amino acid properties, AlignGVGD, Poly Phen2, and SIFT) also suggest that the Asn47Ser variant may not impact the prote in, though this information is not predictive enough to rule out pathogenicity. Although these data supports that this variant may be benign, additional studies are needed to fully assess its clinical significance.

#	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		2	not provided	1	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001157822.1

#	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.140A>G; p.Asn47Ser variant (rs145551875), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 178279). This variant is found on five chromosomes in the African population in the Genome Aggregation Database. The asparagine at codon 47 is moderately conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, due to limited information, the clinical significance of the p.Asn47Ser variant is uncertain at this time.

#	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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