VCV000251936.27 - ClinVar

NM_000527.5(LDLR):c.1617C>T (p.Pro539=)

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.

(18)

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.

Benign

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.1617C>T (p.Pro539=)

Variation ID: 251936 Accession: VCV000251936.27

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19p13.2 19: 11116124 (GRCh38) [ NCBI UCSC ] 19: 11226800 (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 2, 2016	Sep 29, 2024	Feb 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000527.5:c.1617C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000518.1:p.Pro539=	synonymous
NM_001195798.2:c.1617C>T	NP_001182727.1:p.Pro539=	synonymous
NM_001195799.2:c.1494C>T	NP_001182728.1:p.Pro498=	synonymous
NM_001195800.2:c.1113C>T	NP_001182729.1:p.Pro371=	synonymous
NM_001195803.2:c.1236C>T	NP_001182732.1:p.Pro412=	synonymous
NC_000019.10:g.11116124C>T
NC_000019.9:g.11226800C>T
NG_009060.1:g.31744C>T
LRG_274:g.31744C>T
LRG_274t1:c.1617C>T	LRG_274p1:p.Pro539=

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000019.10:11116123: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.

0.12181 (T)

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

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.06405

The Genome Aggregation Database (gnomAD) 0.07003

The Genome Aggregation Database (gnomAD), exomes 0.07562

Trans-Omics for Precision Medicine (TOPMed) 0.07565

Exome Aggregation Consortium (ExAC) 0.07609

1000 Genomes Project 30x 0.11961

1000 Genomes Project 0.12181

Links

ClinGen: CA035425 LDLR-LOVD, British Heart Foundation: LDLR_001186 dbSNP: rs5929 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	4085	4361

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 specified	Benign (3)	criteria provided, multiple submitters, no conflicts	Oct 21, 2016	RCV000243017.9
Hypercholesterolemia, familial, 1	Benign (8)	criteria provided, multiple submitters, no conflicts	Jun 10, 2021	RCV000238018.16
not provided	Benign (2)	criteria provided, multiple submitters, no conflicts	Apr 6, 2016	RCV000589450.2
Smith-Lemli-Opitz syndrome	Benign (1)	no assertion criteria provided	Sep 16, 2020	RCV001275280.1
Familial hypercholesterolemia	Benign (3)	criteria provided, multiple submitters, no conflicts	Feb 1, 2024	RCV001518851.10
Cardiovascular phenotype	Benign (1)	criteria provided, single submitter	Dec 16, 2015	RCV002392747.2

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.
Benign (Mar 25, 2016)	criteria provided, single submitter (ACGS Guidelines, 2013) Method: literature only	Familial hypercholesterolemia Affected status: no Allele origin: germline	LDLR-LOVD, British Heart Foundation Accession: SCV000295539.2 First in ClinVar: Jul 29, 2016 Last updated: May 03, 2018	Publications: PubMed (2) PubMed: 17694954‚ 15701167 Observation 1: Number of individuals with the variant: 1 Observation 2: Number of individuals with the variant: 1
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000304686.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Benign (Mar 01, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Familial hypercholesterolemia Affected status: yes Allele origin: germline	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge Accession: SCV000322964.1 First in ClinVar: Oct 15, 2016 Last updated: Oct 15, 2016	Comment: 8/95 non-FH individuals; MAF = 4,7% in 86 Spanish healthy individuals Observation 1: Comment on evidence: %MAF (ExAC):7.609 Observation 2:
Benign (Oct 21, 2016)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000525634.4 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Comment: This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more) This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
Benign (Jan 12, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Hypercholesterolemia, familial, 1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000410535.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Benign (Apr 06, 2016)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000697205.1 First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018	Publications: PubMed (2) PubMed: 15701167‚ 10208499 Comment: Variant summary: This LDLR c.1617C>T variant affects a non-conserved nucleotide, resulting in synonymous amino acid change. 5/5 splice-site tools via Alamut predict that this variant … (more) Variant summary: This LDLR c.1617C>T variant affects a non-conserved nucleotide, resulting in synonymous amino acid change. 5/5 splice-site tools via Alamut predict that this variant does not affect normal splicing. This variant was found in 9229/121288 control chromosomes from the large and broad populations of ExAC at a frequency of 0.0760916 including several homozygotes, which is over 60 times greater than the maximal expected frequency of a pathogenic LDLR allele (0.0012508), suggesting this variant is benign. The variant has also been reported to co-occur with other potentially pathogenic variants such as c.68-1G>A (internal finding in one specimen), c.1634G>A (internal finding in one specimen), and p. p.Cys667Ser (Zakharova_2005), further supporting the benign outcome. Additionally, the variant is reported in the literature to be a common polymorphism that has no effect on plasma triglyceride, HDL cholesterol, apoA1 or lipoprotein (a) levels (Wu_Atheroscl_1999). Taken together, this variant has been classified as Benign. (less)
Benign (Jul 30, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypercholesterolemia, familial, 1 Affected status: yes Allele origin: germline	Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen Accession: SCV000987007.1 First in ClinVar: Aug 31, 2019 Last updated: Aug 31, 2019	Comment: Due to the increased occurrence of the mutation (>= 5%), this variant is classified as benign.
Benign (Jun 10, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypercholesterolemia, familial, 1 Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV001738000.1 First in ClinVar: Jun 24, 2021 Last updated: Jun 24, 2021	Sex: mixed
Benign (Jun 22, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial hypercholesterolemia Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000689764.2 First in ClinVar: Feb 19, 2018 Last updated: Dec 11, 2022
Benign (Feb 01, 2024)	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: SCV001727625.4 First in ClinVar: Jun 15, 2021 Last updated: Feb 14, 2024
Benign (Dec 16, 2015)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002703202.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more) This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Benign (Jul 15, 2022)	criteria provided, single submitter (Chora et al. (Genet Med. 2022)) Method: clinical testing	Familial hypercholesterolemia Affected status: unknown Allele origin: germline	GENinCode PLC Accession: SCV005073992.1 First in ClinVar: Jul 15, 2024 Last updated: Jul 15, 2024
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005312101.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (-)	no assertion criteria provided Method: research	Familial hypercholesterolemia Affected status: unknown Allele origin: germline	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum Accession: SCV000606467.1 First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017
Benign (-)	no assertion criteria provided Method: clinical testing	Hypercholesterolemia, familial, 1 Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV000733823.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018
Benign (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Smith-Lemli-Opitz syndrome Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001460280.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified 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: SCV001919172.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Benign (Feb 09, 2023)	no assertion criteria provided (ACMG Guidelines, 2015) Method: clinical testing	Familial hypercholesterolemia Affected status: yes Allele origin: germline	Cohesion Phenomics Accession: SCV003836764.1 First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023
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Comment:

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Comment:

Variant summary: This LDLR c.1617C>T variant affects a non-conserved nucleotide, resulting in synonymous amino acid change. 5/5 splice-site tools via Alamut predict that this variant does not affect normal splicing. This variant was found in 9229/121288 control chromosomes from the large and broad populations of ExAC at a frequency of 0.0760916 including several homozygotes, which is over 60 times greater than the maximal expected frequency of a pathogenic LDLR allele (0.0012508), suggesting this variant is benign. The variant has also been reported to co-occur with other potentially pathogenic variants such as c.68-1G>A (internal finding in one specimen), c.1634G>A (internal finding in one specimen), and p. p.Cys667Ser (Zakharova_2005), further supporting the benign outcome. Additionally, the variant is reported in the literature to be a common polymorphism that has no effect on plasma triglyceride, HDL cholesterol, apoA1 or lipoprotein (a) levels (Wu_Atheroscl_1999). Taken together, this variant has been classified as Benign.

Comment:

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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
Use of the denaturing gradient gel electrophoresis (DGGE) method for mutational screening of patients with familial hypercholesterolaemia (FH) and Familial defective apolipoprotein B100 (FDB).	Azian M	The Malaysian journal of pathology	2006	PMID: 17694954
Familial hypercholesterolemia in St-Petersburg: the known and novel mutations found in the low density lipoprotein receptor gene in Russia.	Zakharova FM	BMC medical genetics	2005	PMID: 15701167
Association of 1617 C --> T genetic variation in exon 11 of human low-density lipoprotein receptor and plasma lipid concentration.	Wu JH	Atherosclerosis	1999	PMID: 10208499

Text-mined citations for rs5929 ...

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.1617C>T (p.Pro539=)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs5929 ...