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NM_000527.5(LDLR):c.48C>A (p.Leu16=) AND Hypercholesterolemia, familial, 1

Germline classification:
Likely benign (4 submissions)
Last evaluated:
Nov 7, 2023
Review status:
3 stars out of maximum of 4 stars
reviewed by expert panel
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000238433.6

Allele description [Variation Report for NM_000527.5(LDLR):c.48C>A (p.Leu16=)]

NM_000527.5(LDLR):c.48C>A (p.Leu16=)

Genes:
LDLR-AS1:LDLR antisense RNA 1 [Gene - HGNC]
LDLR:low density lipoprotein receptor [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
19p13.2
Genomic location:
Preferred name:
NM_000527.5(LDLR):c.48C>A (p.Leu16=)
Other names:
NM_000527.5(LDLR):c.48C>A; p.Leu16=
HGVS:
  • NC_000019.10:g.11089596C>A
  • NG_009060.1:g.5216C>A
  • NM_000527.5:c.48C>AMANE SELECT
  • NM_001195798.2:c.48C>A
  • NM_001195799.2:c.48C>A
  • NM_001195800.2:c.48C>A
  • NM_001195803.2:c.48C>A
  • NP_000518.1:p.Leu16=
  • NP_000518.1:p.Leu16=
  • NP_001182727.1:p.Leu16=
  • NP_001182728.1:p.Leu16=
  • NP_001182729.1:p.Leu16=
  • NP_001182732.1:p.Leu16=
  • LRG_274t1:c.48C>A
  • LRG_274:g.5216C>A
  • LRG_274p1:p.Leu16=
  • NC_000019.9:g.11200272C>A
  • NM_000527.4:c.48C>A
  • NR_163945.1:n.64G>T
  • c.48C>A
Links:
LDLR-LOVD, British Heart Foundation: LDLR_001205; dbSNP: rs565675103
NCBI 1000 Genomes Browser:
rs565675103
Molecular consequence:
  • NR_163945.1:n.64G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NM_000527.5:c.48C>A - synonymous variant - [Sequence Ontology: SO:0001819]
  • NM_001195798.2:c.48C>A - synonymous variant - [Sequence Ontology: SO:0001819]
  • NM_001195799.2:c.48C>A - synonymous variant - [Sequence Ontology: SO:0001819]
  • NM_001195800.2:c.48C>A - synonymous variant - [Sequence Ontology: SO:0001819]
  • NM_001195803.2:c.48C>A - synonymous variant - [Sequence Ontology: SO:0001819]
Observations:
2

Condition(s)

Name:
Hypercholesterolemia, familial, 1
Synonyms:
LDL RECEPTOR DISORDER; Hyperlipoproteinemia Type IIa; HYPER-LOW-DENSITY-LIPOPROTEINEMIA; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0007750; MedGen: C0745103; Orphanet: 391665; OMIM: 143890

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000294424LDLR-LOVD, British Heart Foundation
criteria provided, single submitter

(ACGS Guidelines, 2013)		Benign
(Mar 25, 2016) 		germlineliterature only

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV000607407Fundacion Hipercolesterolemia Familiar - SAFEHEART
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain significance
(Mar 1, 2016) 		germlineresearch

PubMed (1)
[See all records that cite this PMID]

SCV004820105All of Us Research Program, National Institutes of Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely Benign
(Dec 1, 2023) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV005375294ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel
reviewed by expert panel

(ClinGen FH ACMG Specifications v1-2)		Likely Benign
(Nov 7, 2023) 		germlinecuration

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown2not providednot provided108544not providedclinical testing, research, curation
not providedgermlineno1not providednot provided1not providedliterature only

Citations

PubMed

An efficient screening procedure detecting six novel mutations in the LDL receptor gene in Swedish children with hypercholesterolemia.

Ekström U, Abrahamson M, Sveger T, Lombardi P, Nilsson-Ehle P.

Hum Genet. 1995 Aug;96(2):147-50.

PubMed [citation]
PMID:
7635461

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000294424.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedliterature only PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineno1not providednot provided1not providednot providednot provided

From Fundacion Hipercolesterolemia Familiar - SAFEHEART, SCV000607407.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedresearch PubMed (1)

Description

%MAF(ExAC):0.00188

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From All of Us Research Program, National Institutes of Health, SCV004820105.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided2not providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown108544not providednot provided2not providednot providednot provided

From ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, SCV005375294.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The NM_000527.5 (LDLR):c.48C>A (p.Leu16=) variant is classified as Likely Benign for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP4, BP4 and BP7 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 7 November 2023. The supporting evidence is as follows: PM2: PopMax MAF=0.00006 in Latino population in gnomAD (gnomAD v2.1.1). PP4: Variant meets PM2 and is identified in 1 index case with possible FH by Simon Broome criteria, after alternative causes of high cholesterol were excluded, from PMID 7635461 (Ekstrom et al., 1995), Sweden. BP4: Variant is synonymous and splicing evaluation is required. Functional data on splicing is not available. MES: A) Not on limits. B) Not on limits. Variant is not predicted to alter splicing. SpliceAI did not predict alternative splicing (? score=0). BP7 met: Variant is synonymous and meets BP4. This variant has 2 supporting evidence codes (BP4, BP7) towards Benign, enough to classify as Likely Benign, and only PM2 and PP4 evidence codes towards Pathogenic, not enough for Likely Pathogenic, so we are confident in classifying this variant as Likely Benign.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 27, 2025