VCV000433236.28 - ClinVar

NM_001171.6(ABCC6):c.1540G>A (p.Val514Ile)

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.

Conflicting classifications of pathogenicity
Uncertain significance(2); Likely benign(4)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001171.6(ABCC6):c.1540G>A (p.Val514Ile)

Variation ID: 433236 Accession: VCV000433236.28

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 16p13.11 16: 16190259 (GRCh38) [ NCBI UCSC ] 16: 16284116 (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	Oct 27, 2017	Oct 20, 2024	Jul 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001171.6:c.1540G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001162.5:p.Val514Ile	missense
NM_001351800.1:c.1198G>A	NP_001338729.1:p.Val400Ile	missense
NR_147784.1:n.1577G>A		non-coding transcript variant
NC_000016.10:g.16190259C>T
NC_000016.9:g.16284116C>T
NG_007558.3:g.38359G>A
LRG_1115:g.38359G>A
LRG_1115t1:c.1540G>A	LRG_1115p1:p.Val514Ile

... more HGVS ... less HGVS

Protein change

V514I, V400I

Other names

Canonical SPDI

NC_000016.10:16190258:C:T

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.

0.00040 (T)

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

1000 Genomes Project 30x 0.00031

1000 Genomes Project 0.00040

The Genome Aggregation Database (gnomAD) 0.00049

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00054

Trans-Omics for Precision Medicine (TOPMed) 0.00069

Exome Aggregation Consortium (ExAC) 0.00098

The Genome Aggregation Database (gnomAD), exomes 0.00106

Links

ClinGen: CA7926273 dbSNP: rs59157279 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.
ABCC6		-	-	GRCh38 GRCh38 GRCh37	1473	1836

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.
Autosomal recessive inherited pseudoxanthoma elasticum	Likely benign (1)	no assertion criteria provided	Feb 2, 2021	RCV000499243.4
not provided	Conflicting interpretations of pathogenicity (4)	criteria provided, conflicting classifications	Jul 1, 2024	RCV001475971.25
Arterial calcification, generalized, of infancy, 2 Autosomal recessive inherited pseudoxanthoma elasticum Pseudoxanthoma elasticum, forme fruste	Likely benign (1)	criteria provided, single submitter	Aug 16, 2021	RCV002496919.2
ABCC6-related disorder	Uncertain significance (1)	criteria provided, single submitter	Oct 30, 2022	RCV004527608.1

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.
Likely benign (Jan 25, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001680173.4 First in ClinVar: Jun 08, 2021 Last updated: Feb 14, 2024
Likely benign (Aug 16, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pseudoxanthoma elasticum, forme fruste Autosomal recessive inherited pseudoxanthoma elasticum Arterial calcification, generalized, of infancy, 2 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002805157.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Uncertain significance (Oct 30, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	ABCC6-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004110608.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The ABCC6 c.1540G>A variant is predicted to result in the amino acid substitution p.Val514Ile. This variant has been previously reported in the heterozygous state in … (more) The ABCC6 c.1540G>A variant is predicted to result in the amino acid substitution p.Val514Ile. This variant has been previously reported in the heterozygous state in an individual with vascular anomalies (Mattassi et al. 2018. PubMed ID: 28655553). This variant has also been identified as a polymorphism in a family with pseudoxanthoma elasticum (Table 2, Miksch. 2005. PubMed ID: 16086317), and it was recently reassessed as likely benign (Verschuere et al. 2021. PubMed ID: 32873932, Supplementary Tables). This variant is reported in 0.31% of alleles in individuals of South Asian descent in gnomAD, including three homozygotes (http://gnomad.broadinstitute.org/variant/16-16284116-C-T). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
Uncertain significance (Oct 29, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003824355.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005213413.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Likely benign (Jul 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV002822289.14 First in ClinVar: Jan 21, 2023 Last updated: Oct 20, 2024	Comment: ABCC6: BP4, BS2 Number of individuals with the variant: 4
Likely benign (Feb 02, 2021)	no assertion criteria provided Method: research	Autosomal recessive inherited pseudoxanthoma elasticum (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	PXE International Accession: SCV000588965.2 First in ClinVar: Oct 27, 2017 Last updated: Feb 07, 2021	Publications: PubMed (2) PubMed: 16086317‚ 32873932

Comment:

The ABCC6 c.1540G>A variant is predicted to result in the amino acid substitution p.Val514Ile. This variant has been previously reported in the heterozygous state in an individual with vascular anomalies (Mattassi et al. 2018. PubMed ID: 28655553). This variant has also been identified as a polymorphism in a family with pseudoxanthoma elasticum (Table 2, Miksch. 2005. PubMed ID: 16086317), and it was recently reassessed as likely benign (Verschuere et al. 2021. PubMed ID: 32873932, Supplementary Tables). This variant is reported in 0.31% of alleles in individuals of South Asian descent in gnomAD, including three homozygotes (http://gnomad.broadinstitute.org/variant/16-16284116-C-T). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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
Reassessment of causality of ABCC6 missense variants associated with pseudoxanthoma elasticum based on Sherloc.	Verschuere S	Genetics in medicine : official journal of the American College of Medical Genetics	2021	PMID: 32873932
Molecular genetics of pseudoxanthoma elasticum: type and frequency of mutations in ABCC6.	Miksch S	Human mutation	2005	PMID: 16086317

Text-mined citations for rs59157279 ...

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 Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_001171.6(ABCC6):c.1540G>A (p.Val514Ile)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs59157279 ...