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NM_000527.5(LDLR):c.314C>T (p.Pro105Leu) AND Hypercholesterolemia, familial, 1

Germline classification:
Uncertain significance (2 submissions)
Last evaluated:
Apr 28, 2023
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
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:
RCV001124032.6

Allele description [Variation Report for NM_000527.5(LDLR):c.314C>T (p.Pro105Leu)]

NM_000527.5(LDLR):c.314C>T (p.Pro105Leu)

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.314C>T (p.Pro105Leu)
HGVS:
  • NC_000019.10:g.11105220C>T
  • NG_009060.1:g.20840C>T
  • NM_000527.5:c.314C>TMANE SELECT
  • NM_001195798.2:c.314C>T
  • NM_001195799.2:c.191C>T
  • NM_001195800.2:c.314-2172C>T
  • NM_001195803.2:c.314-1345C>T
  • NP_000518.1:p.Pro105Leu
  • NP_000518.1:p.Pro105Leu
  • NP_001182727.1:p.Pro105Leu
  • NP_001182728.1:p.Ser64Phe
  • LRG_274t1:c.314C>T
  • LRG_274:g.20840C>T
  • LRG_274p1:p.Pro105Leu
  • NC_000019.9:g.11215896C>T
  • NM_000527.4:c.314C>T
Protein change:
P105L
Links:
dbSNP: rs730882079
NCBI 1000 Genomes Browser:
rs730882079
Molecular consequence:
  • NM_001195800.2:c.314-2172C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001195803.2:c.314-1345C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000527.5:c.314C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.314C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.191C>T - missense variant - [Sequence Ontology: SO:0001583]
Functional consequence:
no known functional consequence - Comment(s)
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
SCV001282937Illumina Laboratory Services, Illumina
criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)		Uncertain significance
(Jan 12, 2018) 		germlineclinical testing

Citation Link,

SCV004820551All of Us Research Program, National Institutes of Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain Significance
(Apr 28, 2023) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown2not providednot provided108544not providedclinical testing

Citations

PubMed

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 Illumina Laboratory Services, Illumina, SCV001282937.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

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

From All of Us Research Program, National Institutes of Health, SCV004820551.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided2not providednot providedclinical testing PubMed (1)

Description

This missense variant (also known as p.Pro84Leu in the mature protein) replaces proline with leucine at codon 105 of the LDLR protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with early-onset myocardial infarction (PMID: Thormaehlen 2015). This variant has been identified in 2/249626 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown108544not providednot provided2not providednot providednot provided

Last Updated: May 7, 2024