NM_000527.5(LDLR):c.1555C>T (p.Pro519Ser) AND Familial hypercholesterolemia

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Dec 9, 2023
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:: RCV003581627.2

Allele description [Variation Report for NM_000527.5(LDLR):c.1555C>T (p.Pro519Ser)]

NM_000527.5(LDLR):c.1555C>T (p.Pro519Ser)

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.1555C>T (p.Pro519Ser)

HGVS:

NC_000019.10:g.11113731C>T
NG_009060.1:g.29351C>T
NM_000527.5:c.1555C>TMANE SELECT
NM_001195798.2:c.1555C>T
NM_001195799.2:c.1432C>T
NM_001195800.2:c.1051C>T
NM_001195803.2:c.1174C>T
NP_000518.1:p.Pro519Ser
NP_000518.1:p.Pro519Ser
NP_001182727.1:p.Pro519Ser
NP_001182728.1:p.Pro478Ser
NP_001182729.1:p.Pro351Ser
NP_001182732.1:p.Pro392Ser
LRG_274t1:c.1555C>T
LRG_274:g.29351C>T
LRG_274p1:p.Pro519Ser
NC_000019.9:g.11224407C>T
NM_000527.4:c.1555C>T
c.1555C>T

Protein change:

P351S

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000212; dbSNP: rs875989923

NCBI 1000 Genomes Browser:

rs875989923

Molecular consequence:

NM_000527.5:c.1555C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1555C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1432C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1051C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1174C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004298362	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Dec 9, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 35047021, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004298362

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Dec 9, 2023)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Low Detection Rates of Genetic FH in Cohort of Patients With Severe Hypercholesterolemia in the United Arabic Emirates.

Rimbert A, Daggag H, Lansberg P, Buckley A, Viel M, Kanninga R, Johansson L, Dullaart RPF, Sinke R, Al Tikriti A, Kuivenhoven JA, Barakat MT.

Front Genet. 2021;12:809256. doi: 10.3389/fgene.2021.809256.

PubMed [citation]

PMID:: 35047021
PMCID:: PMC8762259

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

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004298362.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 519 of the LDLR protein (p.Pro519Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 35047021). ClinVar contains an entry for this variant (Variation ID: 251896). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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