U.S. flag

An official website of the United States government

NM_005157.6(ABL1):c.677A>G (p.Tyr226Cys) AND Congenital heart defects and skeletal malformations syndrome

Germline classification:
Likely pathogenic (2 submissions)
Last evaluated:
Aug 22, 2022
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:
RCV000496944.3

Allele description [Variation Report for NM_005157.6(ABL1):c.677A>G (p.Tyr226Cys)]

NM_005157.6(ABL1):c.677A>G (p.Tyr226Cys)

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.677A>G (p.Tyr226Cys)
HGVS:
  • NC_000009.12:g.130862890A>G
  • NG_012034.1:g.154010A>G
  • NM_005157.6:c.677A>GMANE SELECT
  • NM_007313.3:c.734A>G
  • NP_005148.2:p.Tyr226Cys
  • NP_009297.2:p.Tyr245Cys
  • NP_009297.2:p.Tyr245Cys
  • LRG_769t1:c.677A>G
  • LRG_769t2:c.734A>G
  • LRG_769:g.154010A>G
  • LRG_769p1:p.Tyr226Cys
  • LRG_769p2:p.Tyr245Cys
  • NC_000009.11:g.133738277A>G
  • NM_007313.2:c.734A>G
Protein change:
Y226C; TYR245CYS
Links:
OMIM: 189980.0007; dbSNP: rs1060499547
NCBI 1000 Genomes Browser:
rs1060499547
Molecular consequence:
  • NM_005157.6:c.677A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_007313.3:c.734A>G - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000586799OMIM
no assertion criteria provided
Pathogenic
(Aug 2, 2017) 		germlineliterature only

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

SCV002581798MGZ Medical Genetics Center
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely pathogenic
(Aug 22, 2022) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providedgermlineyes1not providednot providednot providednot providedclinical 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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From OMIM, SCV000586799.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)

Description

In 5 affected individuals from 3 unrelated families with congenital heart defects and skeletal malformations (CHDSKM; 617602), including an African American father and daughter, a European Caucasian father and daughter, and a 5-year-old boy of European Caucasian and Native American descent, Wang et al. (2017) identified heterozygosity for a c.734A-G transition (c.734A-G, NM_007313.2) in the ABL1 gene, resulting in a tyr245-to-cys (Y245C) substitution at a highly conserved residue. The residue, which is 1 of 2 tyrosine residues required for autophosphorylation-induced activation of ABL1 intrinsic kinase activity, is present in both ABL1 isoforms and corresponds to Y226 in isoform 1a. The variant segregated with disease in each of the 3 families, and was shown to have arisen de novo in 2 of them. The authors noted that a similarly affected proband who declined to enter the study was also heterozygous for the Y245C mutation, which was not found in the ExAC database. Immunoblot analysis of transiently transfected HEK293T cells showed increased phosphorylation with the Y245C variant, suggesting increased ABL1 kinase activity.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

From MGZ Medical Genetics Center, SCV002581798.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided1not providednot providednot provided

Last Updated: Jul 15, 2024