VCV000440592.10 - ClinVar

NM_000527.5(LDLR):c.666C>T (p.Cys222=)

Germline

Top reviewed classifications are shown here.

Submission summary:

7 submissions

7 submitters

4 conditions

Reviewed by expert panel

Uncertain significance

Mar 2023 by ClinGen Famili… FDA Recognized Database

for Hypercholesterolemia, familial, 1

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000527.5(LDLR):c.666C>T (p.Cys222=)

Variation ID: 440592 Accession: VCV000440592.10

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19p13.2 19: 11105572 (GRCh38) [ NCBI UCSC ] 19: 11216248 (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 1, 2017	May 1, 2024	Mar 20, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000527.5:c.666C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000518.1:p.Cys222=	synonymous
NM_001195798.2:c.666C>T	NP_001182727.1:p.Cys222=	synonymous
NM_001195799.2:c.543C>T	NP_001182728.1:p.Cys181=	synonymous
NM_001195800.2:c.314-1820C>T		intron variant
NM_001195803.2:c.314-993C>T		intron variant
NC_000019.10:g.11105572C>T
NC_000019.9:g.11216248C>T
NG_009060.1:g.21192C>T
LRG_274:g.21192C>T
LRG_274t1:c.666C>T	LRG_274p1:p.Cys222=

... more HGVS ... less HGVS

Protein change

Other names

NM_000527.5(LDLR):c.666C>T
p.Cys222=

Canonical SPDI

NC_000019.10:11105571: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.

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

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Links

ClinGen: CA505743509 dbSNP: rs756613387 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.
Hypercholesterolemia, familial, 1	Uncertain significance (3)	reviewed by expert panel	Mar 20, 2023	RCV000508956.4
Familial hypercholesterolemia	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Jan 25, 2024	RCV001187844.5
Cardiovascular phenotype	Uncertain significance (1)	criteria provided, single submitter	Oct 27, 2022	RCV002367701.2
not provided	Uncertain significance (1)	criteria provided, single submitter	Aug 9, 2022	RCV003480662.1

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 (Mar 20, 2023)	reviewed by expert panel (ClinGen FH ACMG Specifications v1-2) Method: curation	Hypercholesterolemia, familial, 1 (Semidominant inheritance) Affected status: unknown Allele origin: germline	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel FDA Recognized Database Accession: SCV004022422.1 First in ClinVar: Aug 05, 2023 Last updated: Aug 05, 2023	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/98e5ae0b-297c-4df3-9153-87e79f07cc45 Comment: The NM_000527.5(LDLR):c.666C>T (p.Cys222=) variant is classified as Uncertain significance - conflicting evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, BP4, BP7) as defined by … (more) The NM_000527.5(LDLR):c.666C>T (p.Cys222=) variant is classified as Uncertain significance - conflicting evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, BP4, BP7) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: - PM2: PopMax MAF = 0.000008864 (0.0008864%) in European (non-Finnish) exomes (gnomAD v2.1.1). - BP4: No REVEL, splicing evaluation required. Functional data on splicing not available. B) variant is exonic and at least 50bp downstream from canonical acceptor site and creates GT MES scores: de novo variant = 5.19; canonical donor = 7.67. Ratio de novo variant/canonical donor = 5.19/7.67 = 0.67 --- it is below 0.8 Variant is not predicted to alter splicing. - BP7: Variant is synonymous and meets BP4. (less)
Uncertain significance (Oct 04, 2019)	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: SCV001354736.2 First in ClinVar: Jun 22, 2020 Last updated: Jan 12, 2022	Comment: This synonymous variant does not change the amino acid sequence of the LDLR protein. However, splice site prediction tools suggest that this variant may impact … (more) This synonymous variant does not change the amino acid sequence of the LDLR protein. However, splice site prediction tools suggest that this variant may impact RNA splicing. To our knowledge, functional studies have not been performed to investigate this prediction. This variant has not been reported in individuals affected with familial hypercholesterolemia in the literature. This variant has been identified in 1/249708 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Uncertain significance (Aug 09, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV004224558.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Comment: PP3 Number of individuals with the variant: 2
Uncertain significance (Jan 25, 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: SCV004353331.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Comment: This sequence change affects codon 222 of the LDLR mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid … (more) This sequence change affects codon 222 of the LDLR mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the LDLR protein. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with LDLR-related conditions. ClinVar contains an entry for this variant (Variation ID: 440592). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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 (Dec 01, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypercholesterolemia, familial, 1 (Semidominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004820195.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Comment: This synonymous variant does not change the amino acid sequence of the LDLR protein. However, splice site prediction tools suggest that this variant may impact … (more) This synonymous variant does not change the amino acid sequence of the LDLR protein. However, splice site prediction tools suggest that this variant may impact RNA splicing. To our knowledge, functional studies have not been performed to investigate this prediction. This variant has not been reported in individuals affected with familial hypercholesterolemia in the literature. This variant has been identified in 1/249708 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less) Number of individuals with the variant: 1
Uncertain significance (Oct 27, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002661755.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 32770674 Comment: The c.666C>T variant (also known as p.C222C), located in coding exon 4 of the LDLR gene, results from a C to T substitution at nucleotide … (more) The c.666C>T variant (also known as p.C222C), located in coding exon 4 of the LDLR gene, results from a C to T substitution at nucleotide position 666. This nucleotide substitution does not change the cysteine at codon 222. This variant has been detected in two individuals from a familial hypercholesterolemia cohort (Rieck L et al. Clin Genet, 2020 11;98:457-467). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Pathogenic (-)	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: SCV000606191.1 First in ClinVar: Oct 01, 2017 Last updated: Oct 01, 2017

Comment:

The NM_000527.5(LDLR):c.666C>T (p.Cys222=) variant is classified as Uncertain significance - conflicting evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, BP4, BP7) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: - PM2: PopMax MAF = 0.000008864 (0.0008864%) in European (non-Finnish) exomes (gnomAD v2.1.1). - BP4: No REVEL, splicing evaluation required. Functional data on splicing not available. B) variant is exonic and at least 50bp downstream from canonical acceptor site and creates GT MES scores: de novo variant = 5.19; canonical donor = 7.67. Ratio de novo variant/canonical donor = 5.19/7.67 = 0.67 --- it is below 0.8 Variant is not predicted to alter splicing. - BP7: Variant is synonymous and meets BP4.

Comment:

This synonymous variant does not change the amino acid sequence of the LDLR protein. However, splice site prediction tools suggest that this variant may impact RNA splicing. To our knowledge, functional studies have not been performed to investigate this prediction. This variant has not been reported in individuals affected with familial hypercholesterolemia in the literature. This variant has been identified in 1/249708 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Comment:

This sequence change affects codon 222 of the LDLR mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the LDLR protein. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with LDLR-related conditions. ClinVar contains an entry for this variant (Variation ID: 440592). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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 c.666C>T variant (also known as p.C222C), located in coding exon 4 of the LDLR gene, results from a C to T substitution at nucleotide position 666. This nucleotide substitution does not change the cysteine at codon 222. This variant has been detected in two individuals from a familial hypercholesterolemia cohort (Rieck L et al. Clin Genet, 2020 11;98:457-467). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. 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
Mutation spectrum and polygenic score in German patients with familial hypercholesterolemia.	Rieck L	Clinical genetics	2020	PMID: 32770674
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/98e5ae0b-297c-4df3-9153-87e79f07cc45	-	-	-	-

Text-mined citations for rs756613387 ...

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.666C>T (p.Cys222=)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs756613387 ...