NM_000527.5(LDLR):c.1359-5C>G AND Familial hypercholesterolemia

Germline classification:
Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:
Oct 31, 2023
Review status:
criteria provided, conflicting classifications
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:
RCV001052016.12

Allele description [Variation Report for NM_000527.5(LDLR):c.1359-5C>G]

NM_000527.5(LDLR):c.1359-5C>G

Genes:
LDLR:low density lipoprotein receptor [Gene - OMIM - HGNC]
MIR6886:microRNA 6886 [Gene - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
19p13.2
Genomic location:
Preferred name:
NM_000527.5(LDLR):c.1359-5C>G
HGVS:
  • NC_000019.10:g.11113530C>G
  • NG_009060.1:g.29150C>G
  • NM_000527.5:c.1359-5C>GMANE SELECT
  • NM_001195798.2:c.1359-5C>G
  • NM_001195799.2:c.1236-5C>G
  • NM_001195800.2:c.855-5C>G
  • NM_001195803.2:c.978-5C>G
  • LRG_274t1:c.1359-5C>G
  • LRG_274:g.29150C>G
  • NC_000019.9:g.11224206C>G
  • NM_000527.4:c.1359-5C>G
  • NR_106946.1:n.57C>G
  • c.1359-5C>G
Links:
LDLR-LOVD, British Heart Foundation: LDLR_000192; dbSNP: rs531005522
NCBI 1000 Genomes Browser:
rs531005522
Molecular consequence:
  • NM_000527.5:c.1359-5C>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001195798.2:c.1359-5C>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001195799.2:c.1236-5C>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001195800.2:c.855-5C>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001195803.2:c.978-5C>G - intron variant - [Sequence Ontology: SO:0001627]
  • NR_106946.1:n.57C>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:
Familial hypercholesterolemia
Identifiers:
MONDO: MONDO:0005439; MedGen: C0020445; OMIM: PS143890

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001216204Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Sep 27, 2022) 		germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV001347905Color Diagnostics, LLC DBA Color Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely pathogenic
(Oct 31, 2023) 		germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Hunger and satiety in man.

Hashim SA.

Curr Concepts Nutr. 1977;5:107-18. Review. No abstract available.

PubMed [citation]
PMID:
322946
See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001216204.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change falls in intron 9 of the LDLR gene. It does not directly change the encoded amino acid sequence of the LDLR protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs531005522, gnomAD 0.002%). This variant has been observed in individual(s) with familial hypercholesterolemia (PMID: 19411563, 24627126). ClinVar contains an entry for this variant (Variation ID: 251808). Studies have shown that this variant results in intron 9 inclusion and introduces a premature termination codon (PMID: 19411563). The resulting mRNA is expected to undergo nonsense-mediated decay. 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.

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

From Color Diagnostics, LLC DBA Color Health, SCV001347905.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This variant causes a C>G nucleotide substitution at the -5 position of intron 9 of the LDLR gene. A transcriptional study using RNA from a heterozygous carrier individual has shown that this variant causes a retention of intron 9 and results in a frameshift and premature protein truncation (PMID: 19411563). This variant has been reported in four individuals affected with familial hypercholesterolemia from two unrelated families (PMID: 19411563, 24627126). One affected individual from one of these families was not a carrier (PMID: 19411563). It has been shown that this variant segregates with disease in multiple affected individuals across two families (PMID: 19411563, 24627126; ClinVar SCV000322946.1). This variant has also been reported in one individual affected with myocardial infarction (PMID: 30876530). This variant has been identified in 3/250802 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of LDLR function is a known mechanism of disease. Based on the available evidence, this variant is classified as Likely Pathogenic.

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

Last Updated: Sep 29, 2024