VCV000379777.14 - ClinVar

NM_020297.4(ABCC9):c.3221A>G (p.Asn1074Ser)

Germline

Classification

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.

(7)

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.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_020297.4(ABCC9):c.3221A>G (p.Asn1074Ser)

Variation ID: 379777 Accession: VCV000379777.14

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12p12.1 12: 21844791 (GRCh38) [ NCBI UCSC ] 12: 21997725 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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 8, 2017	May 1, 2024	Nov 28, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_020297.4:c.3221A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_064693.2:p.Asn1074Ser	missense
NM_001377273.1:c.3221A>G	NP_001364202.1:p.Asn1074Ser	missense
NM_001377274.1:c.2354A>G	NP_001364203.1:p.Asn785Ser	missense
NM_005691.2:c.3221A>G
NM_005691.4:c.3221A>G	NP_005682.2:p.Asn1074Ser	missense
NC_000012.12:g.21844791T>C
NC_000012.11:g.21997725T>C
NG_012819.1:g.96904A>G
LRG_377:g.96904A>G
LRG_377t1:c.3221A>G
LRG_377t2:c.3221A>G

... more HGVS ... less HGVS

Protein change

N1074S, N785S

Other names

Canonical SPDI

NC_000012.12:21844790:T:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00002

Links

ClinGen: CA6481186 dbSNP: rs765629988 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help 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.
ABCC9		-	-	GRCh38 GRCh37	1746	1790

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help 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 Help 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 Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Uncertain significance (5)	criteria provided, single submitter	Apr 12, 2017	RCV000419299.5
Dilated cardiomyopathy 1O	Uncertain significance (1)	criteria provided, single submitter	Nov 27, 2023	RCV001042447.8
Cardiovascular phenotype	Uncertain significance (1)	criteria provided, single submitter	Nov 28, 2023	RCV004022321.1

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 Help 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 Help 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 Help 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.
Uncertain significance (Apr 12, 2017)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000517193.4 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Comment: The N1074S variant in the ABCC9 gene has not been reported previously as a pathogenic variant, noras a benign variant, to our knowledge. The N1074S … (more) The N1074S variant in the ABCC9 gene has not been reported previously as a pathogenic variant, noras a benign variant, to our knowledge. The N1074S variant was not observed in approximately 6500individuals of European and African American ancestry in the NHLBI Exome Sequencing Project,indicating it is not a common benign variant in these populations. The N1074S variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Asparagine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. (less)
Uncertain significance (Nov 27, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Dilated cardiomyopathy 1O Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001206127.5 First in ClinVar: Apr 15, 2020 Last updated: Feb 20, 2024	Publications: PubMed (1) PubMed: 30847666 Comment: This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 1074 of the ABCC9 protein (p.Asn1074Ser). … (more) This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 1074 of the ABCC9 protein (p.Asn1074Ser). This variant is present in population databases (rs765629988, gnomAD 0.004%). This missense change has been observed in individual(s) with arrhythmia (PMID: 30847666). ClinVar contains an entry for this variant (Variation ID: 379777). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ABCC9 protein function. 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. (less)
Uncertain significance (Nov 28, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV005023082.1 First in ClinVar: May 01, 2024 Last updated: May 01, 2024	Comment: The p.N1074S variant (also known as c.3221A>G), located in coding exon 25 of the ABCC9 gene, results from an A to G substitution at nucleotide … (more) The p.N1074S variant (also known as c.3221A>G), located in coding exon 25 of the ABCC9 gene, results from an A to G substitution at nucleotide position 3221. The asparagine at codon 1074 is replaced by serine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Study: VKGL Data-share Consensus Accession: SCV001798895.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001923250.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001929312.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001965510.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021

Comment:

The N1074S variant in the ABCC9 gene has not been reported previously as a pathogenic variant, noras a benign variant, to our knowledge. The N1074S variant was not observed in approximately 6500individuals of European and African American ancestry in the NHLBI Exome Sequencing Project,indicating it is not a common benign variant in these populations. The N1074S variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Asparagine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.

Comment:

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 1074 of the ABCC9 protein (p.Asn1074Ser). This variant is present in population databases (rs765629988, gnomAD 0.004%). This missense change has been observed in individual(s) with arrhythmia (PMID: 30847666). ClinVar contains an entry for this variant (Variation ID: 379777). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ABCC9 protein function. 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.

Comment:

The p.N1074S variant (also known as c.3221A>G), located in coding exon 25 of the ABCC9 gene, results from an A to G substitution at nucleotide position 3221. The asparagine at codon 1074 is replaced by serine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Large next-generation sequencing gene panels in genetic heart disease: yield of pathogenic variants and variants of unknown significance.	van Lint FHM	Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation	2019	PMID: 30847666

Text-mined citations for rs765629988 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_020297.4(ABCC9):c.3221A>G (p.Asn1074Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs765629988 ...