NM_003289.4(TPM2):c.463G>A (p.Ala155Thr) AND Arthrogryposis, distal, type 1A

This record was updated by the submitter. Please see the current version.

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Jul 25, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000690257.7

Allele description

NM_003289.4(TPM2):c.463G>A (p.Ala155Thr)

Gene:

TPM2:tropomyosin 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

9p13.3

Genomic location:

Preferred name:

NM_003289.4(TPM2):c.463G>A (p.Ala155Thr)

HGVS:

NC_000009.12:g.35685463C>T
NG_011620.1:g.9595G>A
NM_001301226.2:c.463G>A
NM_001301227.2:c.463G>A
NM_003289.4:c.463G>AMANE SELECT
NM_213674.1:c.463G>A
NP_001288155.1:p.Ala155Thr
NP_001288156.1:p.Ala155Thr
NP_003280.2:p.Ala155Thr
NP_003280.2:p.Ala155Thr
NP_998839.1:p.Ala155Thr
LRG_680t1:c.463G>A
LRG_680t2:c.463G>A
LRG_680:g.9595G>A
LRG_680p1:p.Ala155Thr
LRG_680p2:p.Ala155Thr
NC_000009.11:g.35685460C>T
NM_003289.3:c.463G>A

Protein change:

A155T

Links:

dbSNP: rs1563929039

NCBI 1000 Genomes Browser:

rs1563929039

Molecular consequence:

NM_001301226.2:c.463G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001301227.2:c.463G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_003289.4:c.463G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_213674.1:c.463G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Arthrogryposis, distal, type 1A
Synonyms:: ARTHROGRYPOSIS MULTIPLEX CONGENITA, DISTAL, TYPE I
Identifiers:: MONDO: MONDO:0007157; MedGen: C0220662; Orphanet: 1146; OMIM: 108120

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000817938	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 28, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 33060286, 28492532
SCV004027710	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 25, 2023)	de novo	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

SCV000817938

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 28, 2021)

germline

clinical testing

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

SCV004027710

Institute of Human Genetics, University of Leipzig Medical Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jul 25, 2023)

de novo

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	de novo	yes	not provided	not provided	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

Neurogenetic fetal akinesia and arthrogryposis: genetics, expanding genotype-phenotypes and functional genomics.

Ravenscroft G, Clayton JS, Faiz F, Sivadorai P, Milnes D, Cincotta R, Moon P, Kamien B, Edwards M, Delatycki M, Lamont PJ, Chan SH, Colley A, Ma A, Collins F, Hennington L, Zhao T, McGillivray G, Ghedia S, Chao K, O'Donnell-Luria A, Laing NG, et al.

J Med Genet. 2021 Sep;58(9):609-618. doi: 10.1136/jmedgenet-2020-106901. Epub 2020 Oct 15.

PubMed [citation]

PMID:: 33060286
PMCID:: PMC8328565

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

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000817938.4

#	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 alanine with threonine at codon 155 of the TPM2 protein (p.Ala155Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 569587). This variant has been observed in individual(s) with distal arthrogryposis (PMID: 33060286). This variant is not present in population databases (ExAC no frequency).

#	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 Institute of Human Genetics, University of Leipzig Medical Center, SCV004027710.2

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

Description

Criteria applied: PS3,PS2,PS4_MOD,PM1,PM5,PM2_SUP

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

Last Updated: Feb 14, 2024

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