NM_000527.5(LDLR):c.1576C>T (p.Pro526Ser) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Mar 22, 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:: RCV000161994.16

Allele description [Variation Report for NM_000527.5(LDLR):c.1576C>T (p.Pro526Ser)]

NM_000527.5(LDLR):c.1576C>T (p.Pro526Ser)

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.1576C>T (p.Pro526Ser)

Other names:

FH Cincinnati-3; NM_000527.5(LDLR):c.1576C>T

HGVS:

NC_000019.10:g.11113752C>T
NG_009060.1:g.29372C>T
NM_000527.5:c.1576C>TMANE SELECT
NM_001195798.2:c.1576C>T
NM_001195799.2:c.1453C>T
NM_001195800.2:c.1072C>T
NM_001195803.2:c.1195C>T
NP_000518.1:p.Pro526Ser
NP_000518.1:p.Pro526Ser
NP_001182727.1:p.Pro526Ser
NP_001182728.1:p.Pro485Ser
NP_001182729.1:p.Pro358Ser
NP_001182732.1:p.Pro399Ser
LRG_274t1:c.1576C>T
LRG_274:g.29372C>T
LRG_274p1:p.Pro526Ser
NC_000019.9:g.11224428C>T
NM_000527.4:c.1576C>T
P01130:p.Pro526Ser
c.1576C>T

Protein change:

P358S

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000076; UniProtKB: P01130#VAR_005396; dbSNP: rs730882106

NCBI 1000 Genomes Browser:

rs730882106

Molecular consequence:

NM_000527.5:c.1576C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1576C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1453C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1072C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1195C>T - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

functional variant [Sequence Ontology: SO:0001536] - Comment(s)

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000189569	Dept. of Genetics and Pharmacogenomics, Merck Research Labs	no classification provided (in vitro)	not provided	not applicable	in vitro	PubMed (1) [See all records that cite this PMID]
SCV001134254	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Likely pathogenic (Nov 11, 2022)	unknown	clinical testing	PubMed (10) [See all records that cite these PMIDs] 31345425, 11462246, 27497240, 25647241, 1301956, 9259195, 30586733, 34037665, 31447099, 26467025
SCV001792713	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Mar 22, 2023)	germline	clinical testing	Citation Link,
SCV002501974	AiLife Diagnostics, AiLife Diagnostics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 29, 2021)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 1301956, 25487149, 30586733, 27497240, 25647241, 31447099, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	not applicable	not applicable	not provided	not provided	not provided	not provided	not provided	in vitro
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Risk of Premature Atherosclerotic Disease in Patients With Monogenic Versus Polygenic Familial Hypercholesterolemia.

Trinder M, Li X, DeCastro ML, Cermakova L, Sadananda S, Jackson LM, Azizi H, Mancini GBJ, Francis GA, Frohlich J, Brunham LR.

J Am Coll Cardiol. 2019 Jul 30;74(4):512-522. doi: 10.1016/j.jacc.2019.05.043.

PubMed [citation]

PMID:: 31345425

Identification of recurrent and novel mutations in the LDL receptor gene in German patients with familial hypercholesterolemia.

Nauck MS, Köster W, Dörfer K, Eckes J, Scharnagl H, Gierens H, Nissen H, Nauck MA, Wieland H, März W.

Hum Mutat. 2001 Aug;18(2):165-6.

PubMed [citation]

PMID:: 11462246

See all PubMed Citations (12)

Details of each submission

From Dept. of Genetics and Pharmacogenomics, Merck Research Labs, SCV000189569.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	in vitro	PubMed (1)

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

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV001134254.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

The frequency of this variant in the general population, 0.000023 (3/128988 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with hypercholesterolemia (PMID: 9259195 (1997), 11462246 (2001), 27497240 (2016), 31345425 (2019), 34037665 (2021)). Functional studies have reported that this variant is damaging by causing LDLR activity to decrease to 5% to 15% of wildtype (PMID: 1301956 (1992)) that is likely due to an error in biosynthesis or turnover (PMID: 25647241 (2015)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic.

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

From GeneDx, SCV001792713.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Reported in several individuals with FH, some of which harbored an additional FH-related variant (Hobbs et al., 1992; Day et al., 1997; Nauck et al., 2001; Thormaehlen et al., 2015; Maurer et al., 2016); Also known as p.P505S and FH-Cincinnati-3; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25647241, 27497240, 1301956, 25487149, 9259195, 30586733, 31401775, 31447099, 11462246, 34037665, 31345425, 26582918, 35753512, 10357843, 10208479, 19837725)

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

From AiLife Diagnostics, AiLife Diagnostics, SCV002501974.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (7)

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

Last Updated: Nov 10, 2024

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