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NM_000527.5(LDLR):c.1855T>C (p.Phe619Leu) AND Cardiovascular phenotype

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
May 13, 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:
RCV004020970.2

Allele description [Variation Report for NM_000527.5(LDLR):c.1855T>C (p.Phe619Leu)]

NM_000527.5(LDLR):c.1855T>C (p.Phe619Leu)

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.1855T>C (p.Phe619Leu)
Other names:
NP_000518.1:p.F619L; NM_000527.5(LDLR):c.1855T>C
HGVS:
  • NC_000019.10:g.11120101T>C
  • NG_009060.1:g.35721T>C
  • NM_000527.5:c.1855T>CMANE SELECT
  • NM_001195798.2:c.1855T>C
  • NM_001195799.2:c.1732T>C
  • NM_001195800.2:c.1351T>C
  • NM_001195803.2:c.1474T>C
  • NP_000518.1:p.Phe619Leu
  • NP_000518.1:p.Phe619Leu
  • NP_001182727.1:p.Phe619Leu
  • NP_001182728.1:p.Phe578Leu
  • NP_001182729.1:p.Phe451Leu
  • NP_001182732.1:p.Phe492Leu
  • LRG_274t1:c.1855T>C
  • LRG_274:g.35721T>C
  • LRG_274p1:p.Phe619Leu
  • NC_000019.9:g.11230777T>C
  • NM_000527.4:c.1855T>C
  • c.1855T>C
Protein change:
F451L
Links:
LDLR-LOVD, British Heart Foundation: LDLR_000570; dbSNP: rs747134711
NCBI 1000 Genomes Browser:
rs747134711
Molecular consequence:
  • NM_000527.5:c.1855T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.1855T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.1732T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.1351T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195803.2:c.1474T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Cardiovascular phenotype
Identifiers:
MedGen: CN230736

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV005035803Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Likely pathogenic
(May 13, 2024) 		germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link

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Summary from all submissions

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

Citations

PubMed
See all PubMed Citations (6)

Details of each submission

From Ambry Genetics, SCV005035803.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

The c.1855T>C (p.F619L) alteration is located in exon 13 (coding exon 13) of the LDLR gene. This alteration results from a T to C substitution at nucleotide position 1855, causing the phenylalanine (F) at amino acid position 619 to be replaced by a leucine (L). Based on data from gnomAD, the C allele has an overall frequency of <0.001% (1/251492) total alleles studied. The highest observed frequency was 0.003% (1/30616) of South Asian alleles. This variant (also referred to as p.F598L) has been detected in probands reported to have familial hypercholesterolemia (FH), and co-occurred with a second LDLR variant in an individual with features consistent with homozygous FH (Sun, 1997; Sun, 1998; Taylor, 2007; Tosi, 2007; Paththinige, 2018; Pillai, 2022). This amino acid position is well conserved in available vertebrate species. Studies performed on cultured patient cells with this variant showed reduced LDLR expression and activity (Sun, 1997). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.

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

Last Updated: Sep 29, 2024