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NM_000527.5(LDLR):c.1981C>G (p.Pro661Ala) AND Hypercholesterolemia, familial, 1

Germline classification:
Uncertain significance (2 submissions)
Last evaluated:
Mar 24, 2024
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV001000104.2

Allele description [Variation Report for NM_000527.5(LDLR):c.1981C>G (p.Pro661Ala)]

NM_000527.5(LDLR):c.1981C>G (p.Pro661Ala)

Gene:
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.1981C>G (p.Pro661Ala)
HGVS:
  • NC_000019.10:g.11120227C>G
  • NG_009060.1:g.35847C>G
  • NM_000527.5:c.1981C>GMANE SELECT
  • NM_001195798.2:c.1981C>G
  • NM_001195799.2:c.1858C>G
  • NM_001195800.2:c.1477C>G
  • NM_001195803.2:c.1600C>G
  • NP_000518.1:p.Pro661Ala
  • NP_001182727.1:p.Pro661Ala
  • NP_001182728.1:p.Pro620Ala
  • NP_001182729.1:p.Pro493Ala
  • NP_001182732.1:p.Pro534Ala
  • LRG_274t1:c.1981C>G
  • LRG_274:g.35847C>G
  • NC_000019.9:g.11230903C>G
  • NC_000019.9:g.11230903C>G
  • NM_000527.4:c.1981C>G
Protein change:
P493A
Links:
dbSNP: rs1182317785
NCBI 1000 Genomes Browser:
rs1182317785
Molecular consequence:
  • NM_000527.5:c.1981C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.1981C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.1858C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.1477C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195803.2:c.1600C>G - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

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
SCV001156525Fundacion Favaloro, PRICAI
no assertion criteria provided
Likely pathogenic
(May 29, 2019) 		unknownresearch

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

SCV005427634All of Us Research Program, National Institutes of Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain Significance
(Mar 24, 2024) 		germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided143475not providedclinical testing
not providedunknownyesnot providednot providednot providednot providednot providedresearch

Citations

PubMed

Functional analysis of six uncharacterised mutations in LDLR gene.

Gomez A, Colombo R, Pontoglio A, Helman L, Kaeser L, Giunta G, Parolin ML, Toscanini U, Cuniberti L.

Atherosclerosis. 2019 Dec;291:44-51. doi: 10.1016/j.atherosclerosis.2019.10.013. Epub 2019 Oct 12.

PubMed [citation]
PMID:
31689621

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 Fundacion Favaloro, PRICAI, SCV001156525.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedresearch PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot providednot providednot providednot providednot provided

From All of Us Research Program, National Institutes of Health, SCV005427634.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (2)

Description

This missense variant replaces proline with alanine at codon 661 of the LDLR protein. This variant is also known as p.Pro640Ala in the mature protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. An in vitro functional study using transfected heterologous cells has shown that this variant causes a 50-60% reduction in LDL uptake (PMID: 31689621). This variant has been reported in one individual affected with familial hypercholesterolemia (PMID: 31689621). This variant has not been identified 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown143475not providednot provided1not providednot providednot provided

Last Updated: Mar 5, 2025