ClinVar Genomic variation as it relates to human health
NM_005157.6(ABL1):c.1009G>A (p.Ala337Thr)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_005157.6(ABL1):c.1009G>A (p.Ala337Thr)
Variation ID: 374794 Accession: VCV000374794.7
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9q34.12 9: 130872961 (GRCh38) [ NCBI UCSC ] 9: 133748348 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Mar 17, 2017 Feb 14, 2024 Oct 31, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_005157.6:c.1009G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005148.2:p.Ala337Thr missense NM_007313.3:c.1066G>A NP_009297.2:p.Ala356Thr missense NC_000009.12:g.130872961G>A NC_000009.11:g.133748348G>A NG_012034.1:g.164081G>A LRG_769:g.164081G>A LRG_769t1:c.1009G>A LRG_769p1:p.Ala337Thr LRG_769t2:c.1066G>A LRG_769p2:p.Ala356Thr - Protein change
- A337T, A356T
- Other names
- p.Ala337Thr
- Canonical SPDI
- NC_000009.12:130872960:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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ABL1 | - | - |
GRCh38 GRCh37 |
546 | 606 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Oct 31, 2023 | RCV000496371.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 11, 2016 | RCV000445566.1 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 19, 2021 | RCV000492810.5 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Dec 11, 2016)
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criteria provided, single submitter
Method: clinical testing
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Congenital heart disease
Abnormal skeletal morphology failure to gain weight (Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Baylor Genetics
Accession: SCV000485097.1
First in ClinVar: Mar 17, 2017 Last updated: Mar 17, 2017 |
Comment:
This variant was seen once in our laboratory de novo in a 1-year-old male with IUGR, atrial septal defect, diaphragmatic hernia, microcephaly, failure to thrive, … (more)
This variant was seen once in our laboratory de novo in a 1-year-old male with IUGR, atrial septal defect, diaphragmatic hernia, microcephaly, failure to thrive, dysmorphic features, short stature, pectus excavatum, 2-3 toe syndactyly, imperforate anus, unilateral undescended testicle. (less)
Clinical Features:
Short stature (present) , Fetal growth restriction (present) , Frontal bossing (present) , Broad eyebrow (present) , Unilateral ptosis (present) , Upslanted palpebral fissure (present) … (more)
Short stature (present) , Fetal growth restriction (present) , Frontal bossing (present) , Broad eyebrow (present) , Unilateral ptosis (present) , Upslanted palpebral fissure (present) , Narrow mouth (present) , Thin vermilion border (present) , Macrotia (present) , Micrognathia (present) , Dimple chin (present) , Microcephaly (present) , Atrial septal defect (present) , Pectus excavatum (present) , Clinodactyly of the 5th finger (present) , 2-3 toe syndactyly (present) , Flexion contracture (present) , Thin skin (present) , Cutis marmorata (present) , Pneumothorax (present) , Congenital diaphragmatic hernia (present) , Imperforate anus (present) , Cryptorchidism (present) (less)
Age: 0-9 years
Sex: male
Ethnicity/Population group: Middle Eastern
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Pathogenic
(Jul 03, 2018)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000581893.4
First in ClinVar: Jul 02, 2017 Last updated: Apr 17, 2019 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Jan 01, 2020)
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criteria provided, single submitter
Method: clinical testing, in vitro
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Congenital heart defects and skeletal malformations syndrome
Affected status: yes, not applicable
Allele origin:
de novo,
not applicable
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Human Development and Health, University of Southampton
Accession: SCV001441170.1
First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020 |
Observation 1: Observation 2: Observation 3:
Method: Western blotting following transient transfection of cell lines with mutagenised ABL1 cDNA plasmid constructs
Result:
Increased ABL1 tyrosine kinase activity demonstrated
Observation 4:
Method: Western blotting following transient transfection of cell lines with mutagenised ABL1 cDNA plasmid constructs
Result:
Increased ABL1 tyrosine kinase activity demonstrated
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Pathogenic
(Aug 19, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002234666.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Oct 31, 2023)
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criteria provided, single submitter
Method: clinical testing
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Congenital heart defects and skeletal malformations syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV004100842.1
First in ClinVar: Nov 11, 2023 Last updated: Nov 11, 2023 |
Comment:
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 … (more)
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. (less)
Age: 0-9 years
Sex: female
Method: DNA was used to perform targeted gene capture using a custom capture kit. Libraries were sequenced to mean >80-100X coverage on the Illumina sequencing platform. Sequence obtained were aligned to human references genome using BWA program and analyzed using Picard and GATK-Lite toolkit to identify variants in the targeted genes relevant to clinical indication.
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Pathogenic
(Nov 11, 2021)
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no assertion criteria provided
Method: literature only
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CONGENITAL HEART DEFECTS AND SKELETAL MALFORMATIONS SYNDROME
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000586800.2
First in ClinVar: Aug 07, 2017 Last updated: Nov 20, 2021 |
Comment on evidence:
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 … (more)
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. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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The expanding clinical phenotype of germline ABL1-associated congenital heart defects and skeletal malformations syndrome. | Chen CA | Human mutation | 2020 | PMID: 32643838 |
Germline mutations in ABL1 cause an autosomal dominant syndrome characterized by congenital heart defects and skeletal malformations. | Wang X | Nature genetics | 2017 | PMID: 28288113 |
Text-mined citations for rs1060499548 ...
HelpRecord last updated Feb 14, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.