VCV002568142.2 - ClinVar

NM_000527.5(LDLR):c.2473_2475del (p.Asn825del)

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.

(1)

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.

Likely pathogenic

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000527.5(LDLR):c.2473_2475del (p.Asn825del)

Variation ID: 2568142 Accession: VCV002568142.2

Type and length

Deletion, 3 bp

Location

Cytogenetic: 19p13.2 19: 11129594-11129596 (GRCh38) [ NCBI UCSC ] 19: 11240270-11240272 (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	Jul 8, 2023	May 1, 2024	Apr 18, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000527.5:c.2473_2475del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000518.1:p.Asn825del	inframe deletion
NM_001195798.2:c.2473_2475del	NP_001182727.1:p.Asn825del	inframe deletion
NM_001195799.2:c.2350_2352del	NP_001182728.1:p.Asn784del	inframe deletion
NM_001195800.2:c.1969_1971del	NP_001182729.1:p.Asn657del	inframe deletion
NM_001195803.2:c.1939_1941del	NP_001182732.1:p.Asn647del	inframe deletion
NC_000019.10:g.11129596_11129598del
NC_000019.9:g.11240272_11240274del
NG_009060.1:g.45216_45218del
LRG_274:g.45216_45218del
LRG_274t1:c.2473_2475del	LRG_274p1:p.Asn825del

... more HGVS ... less HGVS

Protein change

N647del, N784del, N825del, N657del

Other names

Canonical SPDI

NC_000019.10:11129593:ACAAC:AC

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.

Links

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.
LDLR		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	4076	4352

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.
Cardiovascular phenotype	Likely pathogenic (1)	criteria provided, single submitter	Apr 18, 2023	RCV003283510.2

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 pathogenic (Apr 18, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV004007168.2 First in ClinVar: Jul 08, 2023 Last updated: May 01, 2024	Comment: The c.2473_2475delAAC variant (also known as p.N825del) is located in coding exon 17 of the LDLR gene. This variant results from an in-frame AAC deletion … (more) The c.2473_2475delAAC variant (also known as p.N825del) is located in coding exon 17 of the LDLR gene. This variant results from an in-frame AAC deletion at nucleotide positions 2473 to 2475. This results in the in-frame deletion of an asparagine at codon 825. This amino acid position is highly conserved in available vertebrate species and the impacted region is critical for protein function (Ambry internal data). In addition, this alteration has been observed in at least one individual with a personal history that is consistent with LDLR-related disease (Ambry internal data). In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)

Comment:

The c.2473_2475delAAC variant (also known as p.N825del) is located in coding exon 17 of the LDLR gene. This variant results from an in-frame AAC deletion at nucleotide positions 2473 to 2475. This results in the in-frame deletion of an asparagine at codon 825. This amino acid position is highly conserved in available vertebrate species and the impacted region is critical for protein function (Ambry internal data). In addition, this alteration has been observed in at least one individual with a personal history that is consistent with LDLR-related disease (Ambry internal data). In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for this variant ...

Record last updated May 01, 2024

ClinVar Genomic variation as it relates to human health

NM_000527.5(LDLR):c.2473_2475del (p.Asn825del)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...