NM_005157.6(ABL1):c.1009G>A (p.Ala337Thr) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Aug 19, 2021
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:: RCV000492810.6

Allele description [Variation Report for NM_005157.6(ABL1):c.1009G>A (p.Ala337Thr)]

NM_005157.6(ABL1):c.1009G>A (p.Ala337Thr)

Gene:

ABL1:ABL proto-oncogene 1, non-receptor tyrosine kinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

9q34.12

Genomic location:

Preferred name:

NM_005157.6(ABL1):c.1009G>A (p.Ala337Thr)

Other names:

p.Ala337Thr

HGVS:

NC_000009.12:g.130872961G>A
NG_012034.1:g.164081G>A
NM_005157.6:c.1009G>AMANE SELECT
NM_007313.3:c.1066G>A
NP_005148.2:p.Ala337Thr
NP_009297.2:p.Ala356Thr
NP_009297.2:p.Ala356Thr
LRG_769t1:c.1009G>A
LRG_769t2:c.1066G>A
LRG_769:g.164081G>A
LRG_769p1:p.Ala337Thr
LRG_769p2:p.Ala356Thr
NC_000009.11:g.133748348G>A
NM_007313.2:c.1066G>A

Protein change:

A337T; ALA356THR

Links:

OMIM: 189980.0008; dbSNP: rs1060499548

NCBI 1000 Genomes Browser:

rs1060499548

Molecular consequence:

NM_005157.6:c.1009G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_007313.3:c.1066G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000581893	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Pathogenic (Jul 3, 2018)	germline	clinical testing	Citation Link,
SCV002234666	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 19, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 28288113, 32643838, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000581893

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Pathogenic
(Jul 3, 2018)

germline

clinical testing

Citation Link,

SCV002234666

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 19, 2021)

germline

clinical testing

PubMed (3)
[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	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

Germline mutations in ABL1 cause an autosomal dominant syndrome characterized by congenital heart defects and skeletal malformations.

Wang X, Charng WL, Chen CA, Rosenfeld JA, Al Shamsi A, Al-Gazali L, McGuire M, Mew NA, Arnold GL, Qu C, Ding Y, Muzny DM, Gibbs RA, Eng CM, Walkiewicz M, Xia F, Plon SE, Lupski JR, Schaaf CP, Yang Y.

Nat Genet. 2017 Apr;49(4):613-617. doi: 10.1038/ng.3815. Epub 2017 Mar 13.

PubMed [citation]

PMID:: 28288113
PMCID:: PMC5373987

The expanding clinical phenotype of germline ABL1-associated congenital heart defects and skeletal malformations syndrome.

Chen CA, Crutcher E, Gill H, Nelson TN, Robak LA, Jongmans MCJ, Pfundt R, Prasad C, Berard RA, Fannemel M, Frengen E, Misceo D, Ramsey K, Yang Y, Schaaf CP, Wang X.

Hum Mutat. 2020 Oct;41(10):1738-1744. doi: 10.1002/humu.24075. Epub 2020 Jul 19.

PubMed [citation]

PMID:: 32643838

See all PubMed Citations (3)

Details of each submission

From GeneDx, SCV000581893.4

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

Description

The A356T pathogenic variant in the ABL1 gene has been reported previously as a de novo variant in an individual with features of ABL1-related disorder (Wang et al., 2017). The A356T variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The A356T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. Functional studies indicate that the A356T variant is associated with increased tyrosine phosphorylation (Wang et al., 2017). We interpret A356T as a pathogenic variant.

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV002234666.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ABL1 function (PMID: 28288113). 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 ABL1 protein function. ClinVar contains an entry for this variant (Variation ID: 374794). This missense change has been observed in individual(s) with congenital heart defects and skeletal malformations syndrome (PMID: 28288113, 32643838). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with threonine at codon 356 of the ABL1 protein (p.Ala356Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine.

#	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

ClinVar

Relating variation to medicine