VCV000226383.14 - ClinVar

NM_000527.5(LDLR):c.2027del (p.Gly676fs)

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.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000527.5(LDLR):c.2027del (p.Gly676fs)

Variation ID: 226383 Accession: VCV000226383.14

Type and length

Deletion, 1 bp

Location

Cytogenetic: 19p13.2 19: 11120408 (GRCh38) [ NCBI UCSC ] 19: 11231084 (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	May 22, 2016	May 1, 2024	Mar 26, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000527.5:c.2027del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000518.1:p.Gly676fs	frameshift
NM_000527.4:c.2027delG
NM_001195798.2:c.2027del	NP_001182727.1:p.Gly676fs	frameshift
NM_001195799.2:c.1904del	NP_001182728.1:p.Gly635fs	frameshift
NM_001195800.2:c.1523del	NP_001182729.1:p.Gly508fs	frameshift
NM_001195803.2:c.1606+176del		intron variant
NC_000019.10:g.11120409del
NC_000019.9:g.11231085del
NG_009060.1:g.36029del
LRG_274:g.36029del
LRG_274t1:c.2027del	LRG_274p1:p.Gly676fs

... more HGVS ... less HGVS

Protein change

G508fs, G635fs, G676fs

Other names

p.Gly676Alafs*33

Canonical SPDI

NC_000019.10:11120407:GG:G

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

ClinGen: CA10576327 dbSNP: rs875989937 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	4075	4351

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.
Hypercholesterolemia, familial, 1	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Mar 26, 2024	RCV000211640.14
not provided	Pathogenic (1)	criteria provided, single submitter	Dec 29, 2021	RCV001843946.4
Cardiovascular phenotype	Pathogenic (1)	criteria provided, single submitter	Apr 5, 2016	RCV002415888.2

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.
Pathogenic (Mar 27, 2018)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Familial hypercholesterolemia Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000544693.3 First in ClinVar: May 22, 2016 Last updated: Oct 10, 2018	Publications: PubMed (1) PubMed: 28492532 Comment: This sequence change creates a premature translational stop signal (p.Gly676Alafs33) in the LDLR gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Gly676Alafs33) in the LDLR gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with hypercholesterolemia in several families (PMID:Â¬â€ 25839937,Â¬â€ 26688439). ClinVar contains an entry for this variant (Variation ID: 226383). Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Dec 29, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV002103279.1 First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022	Publications: PubMed (4) PubMed: 25839937‚ 26688439‚ 32489792‚ 34249980 Comment: PP1_strong, PM2, PM3, PS4_moderate, PVS1
Pathogenic (Mar 24, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypercholesterolemia, familial, 1 Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002017123.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Apr 05, 2016)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002717991.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 26688439 Comment: The c.2027delG pathogenic mutation, located in coding exon 14 of the LDLR gene, results from a deletion of one nucleotide at nucleotide position 2027, causing … (more) The c.2027delG pathogenic mutation, located in coding exon 14 of the LDLR gene, results from a deletion of one nucleotide at nucleotide position 2027, causing a translational frameshift with a predicted alternate stop codon (p.G676Afs*33). This recurrent frameshift mutation has been reported in several Saudi families with heterozygous or homozygous familial hypercholesterolemia (Al-Allaf FA et al. Genomics 2016;107(1):24-32). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
Pathogenic (Mar 26, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypercholesterolemia, familial, 1 Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004807028.1 First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024
Pathogenic (Jun 03, 2015)	no assertion criteria provided Method: clinical testing	Familial hypercholesterolemia Affected status: yes Allele origin: germline	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital Accession: SCV000268652.1 First in ClinVar: May 22, 2016 Last updated: May 22, 2016	Number of individuals with the variant: 1
Pathogenic (Feb 05, 2020)	no assertion criteria provided Method: clinical testing	Hypercholesterolemia, familial, 1 Affected status: yes Allele origin: germline	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City Accession: SCV001190744.1 First in ClinVar: Mar 29, 2020 Last updated: Mar 29, 2020

Comment:

This sequence change creates a premature translational stop signal (p.Gly676Alafs*33) in the LDLR gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with hypercholesterolemia in several families (PMID:Â¬â€ 25839937,Â¬â€ 26688439). ClinVar contains an entry for this variant (Variation ID: 226383). Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525). For these reasons, this variant has been classified as Pathogenic.

Comment:

The c.2027delG pathogenic mutation, located in coding exon 14 of the LDLR gene, results from a deletion of one nucleotide at nucleotide position 2027, causing a translational frameshift with a predicted alternate stop codon (p.G676Afs*33). This recurrent frameshift mutation has been reported in several Saudi families with heterozygous or homozygous familial hypercholesterolemia (Al-Allaf FA et al. Genomics 2016;107(1):24-32). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

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
Saudi Familial Hypercholesterolemia Patients With Rare LDLR Stop Gain Variant Showed Variable Clinical Phenotype and Resistance to Multiple Drug Regimen.	Awan ZA	Frontiers in medicine	2021	PMID: 34249980
Xanthomas Can Be Misdiagnosed and Mistreated in Homozygous Familial Hypercholesterolemia Patients: A Call for Increased Awareness Among Dermatologists and Health Care Practitioners.	Alnouri F	Global heart	2020	PMID: 32489792
Identification of a recurrent frameshift mutation at the LDLR exon 14 (c.2027delG, p.(G676Afs*33)) causing familial hypercholesterolemia in Saudi Arab homozygous children.	Al-Allaf FA	Genomics	2016	PMID: 26688439
Next generation sequencing to identify novel genetic variants causative of autosomal dominant familial hypercholesterolemia associated with increased risk of coronary heart disease.	Al-Allaf FA	Gene	2015	PMID: 25839937

Text-mined citations for rs875989937 ...

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_000527.5(LDLR):c.2027del (p.Gly676fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs875989937 ...