NM_005157.6(ABL1):c.1009G>A (p.Ala337Thr) AND Congenital heart defects and skeletal malformations syndrome

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Oct 31, 2023
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:: RCV000496371.5

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]

Observations:

Condition(s)

Name:: Congenital heart defects and skeletal malformations syndrome
Identifiers:: MONDO: MONDO:0060532; MedGen: C4539857; OMIM: 617602

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000586800	OMIM	no assertion criteria provided	Pathogenic (Nov 11, 2021)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 28288113, 32643838
SCV001441170	Human Development and Health, University of Southampton	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 1, 2020)	de novo, not applicable	clinical testing, in vitro	PubMed (1) [See all records that cite this PMID]
SCV004100842	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 31, 2023)	germline	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

SCV000586800

OMIM

no assertion criteria provided

Pathogenic
(Nov 11, 2021)

germline

literature only

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

SCV001441170

Human Development and Health, University of Southampton

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 1, 2020)

de novo, not applicable

clinical testing, in vitro

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

SCV004100842

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Oct 31, 2023)

germline

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	not applicable	not applicable	not provided	not provided	not provided	not provided	not provided	in vitro
not provided	de novo	yes	2	not provided	not provided	2	not provided	clinical testing
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

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 OMIM, SCV000586800.2

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

Description

In a 1-year-old Arab boy with congenital heart defects and skeletal malformations syndrome (CHDSKM; 617602), Wang et al. (2017) identified heterozygosity for a de novo c.1066G-A transition (c.1066G-A, NM_007313.2) in the ABL1 gene, resulting in an ala356-to-thr (A356T) substitution at a highly conserved residue within the myristoyl-binding site of the ABL1 kinase domain. The residue is present in both ABL1 isoforms, and corresponds to A337 in isoform 1a. Immunoblot analysis of transiently transfected HEK293T cells showed increased phosphorylation with the mutant in both isoforms, suggesting increased ABL1 kinase activity.

In 3 unrelated patients (patients 4, 5, and 6) with CHDSKM, Chen et al. (2020) identified heterozygosity for the A356T mutation in the ABL1 gene, which arose de novo in all 3 probands. Functional analysis in transiently transfected HEK293T cells demonstrated that overexpression of the A356T mutant resulted in increased overall phosphotyrosine levels as well as increased autophosphorylation of ABL1 itself compared to wildtype protein.

#	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		not provided	not provided	not provided	not provided

From Human Development and Health, University of Southampton, SCV001441170.1

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

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

From Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics, SCV004100842.1

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

Description

A heterozygous missense variant in exon 6 of the ABL1 gene that results in the amino acid substitution of Threonine for Alanine at codon 337 (p.Ala337Thr) was detected. This variant has not been reported in the 1000 genomes, gnomAD (v3.1), gnomdAD (v2.1) and topmed databases. The in-silico predictions of the variant are probably damaging by PolyPhen-2 (HumDiv), and damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic.

#	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		1	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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