VCV000251429.2 - ClinVar

NM_000527.5(LDLR):c.743G>A (p.Cys248Tyr)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Likely pathogenic

2 out of 2 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000527.5(LDLR):c.743G>A (p.Cys248Tyr)

Variation ID: 251429 Accession: VCV000251429.2

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19p13.2 19: 11106613 (GRCh38) [ NCBI UCSC ] 19: 11217289 (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 29, 2016	Jul 5, 2025	Jun 19, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_000527.5:c.743G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000518.1:p.Cys248Tyr	missense
NM_001195798.2:c.743G>A	NP_001182727.1:p.Cys248Tyr	missense
NM_001195799.2:c.620G>A	NP_001182728.1:p.Cys207Tyr	missense
NM_001195800.2:c.314-779G>A		intron variant
NM_001195803.2:c.362G>A	NP_001182732.1:p.Cys121Tyr	missense
NC_000019.10:g.11106613G>A
NC_000019.9:g.11217289G>A
NG_009060.1:g.22233G>A
LRG_274:g.22233G>A
	P01130:p.Cys248Tyr

... more HGVS ... less HGVS

Protein change

C248Y, C121Y, C207Y

Other names

Canonical SPDI

NC_000019.10:11106612:G:A

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: CA10585109 LDLR-LOVD, British Heart Foundation: LDLR_000407 UniProtKB: P01130#VAR_005345 dbSNP: rs879254663 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	4523	4861

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	Likely pathogenic (1)	criteria provided, single submitter	Mar 25, 2016	RCV000237638.1
Familial hypercholesterolemia	Likely pathogenic (1)	criteria provided, single submitter	Jun 19, 2025	RCV005431572.1

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.	Expand all rows Collapse all rows 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 (Mar 25, 2016) C Contributing to aggregate classification	criteria provided, single submitter (ACGS Guidelines, 2013)	Familial hypercholesterolemia (Autosomal dominant inheritance)	LDLR-LOVD, British Heart Foundation Accession: SCV000294946.2 First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016	Publications: PubMed (1) PubMed: 9026534 Observation: 1 Collection method: literature only Allele origin: germline Affected status: yes more Observation 1 Collection method: literature only Allele origin: germline Affected status: yes Number of individuals with the variant: 1

Likely pathogenic (Jun 19, 2025) C Contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Familial hypercholesterolemia	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV006101605.1 First in ClinVar: Jul 05, 2025 Last updated: Jul 05, 2025	Publications: PubMed (2) PubMed: 36325061‚ 9026534 Comment: show Variant summary: LDLR c.743G>A (p.Cys248Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant was absent in 251486 control chromosomes. c.743G>A has been observed in at-least three individuals affected with autosomal recessive Familial Hypercholesterolemia (Du_2022, Webb_1996). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in likely 10%-<30% of normal activity in the lymphoblasts from the patient carrying the currant variant and the in-trans pathogenic p.Arg350Pro (Webb_1996, PMID 15100232). The following publications have been ascertained in the context of this evaluation (PMID: 36325061, 9026534). ClinVar contains an entry for this variant (Variation ID: 251429). Based on the evidence outlined above, the variant was classified as likely pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Comment:

Variant summary: LDLR c.743G>A (p.Cys248Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant was absent in 251486 control chromosomes. c.743G>A has been observed in at-least three individuals affected with autosomal recessive Familial Hypercholesterolemia (Du_2022, Webb_1996). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in likely 10%-<30% of normal activity in the lymphoblasts from the patient carrying the currant variant and the in-trans pathogenic p.Arg350Pro (Webb_1996, PMID 15100232). The following publications have been ascertained in the context of this evaluation (PMID: 36325061, 9026534). ClinVar contains an entry for this variant (Variation ID: 251429). Based on the evidence outlined above, the variant was classified as likely pathogenic.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Low-density lipoprotein receptor genotypes modify the sera metabolome of patients with homozygous familial hypercholesterolemia.	Du Z	iScience	2022	PMID: 36325061
Characterization of mutations in the low density lipoprotein (LDL)-receptor gene in patients with homozygous familial hypercholesterolemia, and frequency of these mutations in FH patients in the United Kingdom.	Webb JC	Journal of lipid research	1996	PMID: 9026534

Text-mined citations for rs879254663 ...

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 Apr 04, 2026