NM_000527.5(LDLR):c.367T>C (p.Ser123Pro) AND Familial hypercholesterolemia

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Feb 19, 2024
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:: RCV001042933.7

Allele description [Variation Report for NM_000527.5(LDLR):c.367T>C (p.Ser123Pro)]

NM_000527.5(LDLR):c.367T>C (p.Ser123Pro)

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.367T>C (p.Ser123Pro)

HGVS:

NC_000019.10:g.11105273T>C
NG_009060.1:g.20893T>C
NM_000527.5:c.367T>CMANE SELECT
NM_001195798.2:c.367T>C
NM_001195799.2:c.244T>C
NM_001195800.2:c.314-2119T>C
NM_001195803.2:c.314-1292T>C
NP_000518.1:p.Ser123Pro
NP_000518.1:p.Ser123Pro
NP_001182727.1:p.Ser123Pro
NP_001182728.1:p.Ser82Pro
LRG_274t1:c.367T>C
LRG_274:g.20893T>C
LRG_274p1:p.Ser123Pro
NC_000019.9:g.11215949T>C
NM_000527.4:c.367T>C
c.367T>C
p.(Ser123Pro)

Protein change:

S123P

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001226; dbSNP: rs879254495

NCBI 1000 Genomes Browser:

rs879254495

Molecular consequence:

NM_001195800.2:c.314-2119T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.314-1292T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.367T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.367T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.244T>C - 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
SCV000294662	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Uncertain significance (Feb 19, 2024)	germline	literature only	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001206642	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 2, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 19446849, 20045108, 34297352, 36229376, 15015036, 28492532
SCV001353457	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 1, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000294662

LDLR-LOVD, British Heart Foundation

criteria provided, single submitter

(ACGS Guidelines, 2013)

Uncertain significance
(Feb 19, 2024)

germline

literature only

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

Citation Link,

SCV001206642

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 2, 2023)

germline

clinical testing

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

SCV001353457

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Dec 1, 2019)

germline

clinical testing

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

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	1	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

The type of LDLR gene mutation predicts cardiovascular risk in children with familial hypercholesterolemia.

Guardamagna O, Restagno G, Rolfo E, Pederiva C, Martini S, Abello F, Baracco V, Pisciotta L, Pino E, Calandra S, Bertolini S.

J Pediatr. 2009 Aug;155(2):199-204.e2. doi: 10.1016/j.jpeds.2009.02.022. Epub 2009 May 15.

PubMed [citation]

PMID:: 19446849

Identification and functional characterization of LDLR mutations in familial hypercholesterolemia patients from Southern Italy.

Romano M, Di Taranto MD, D'Agostino MN, Marotta G, Gentile M, Abate G, Mirabelli P, Di Noto R, Del Vecchio L, Rubba P, Fortunato G.

Atherosclerosis. 2010 Jun;210(2):493-6. doi: 10.1016/j.atherosclerosis.2009.11.051. Epub 2009 Dec 5.

PubMed [citation]

PMID:: 20045108

See all PubMed Citations (7)

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000294662.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	literature only	PubMed (1)

Description

Reevaluation of the ACMG criteria for this entry, only PM2 can be scored. Therefore, the classification is for Uncertain significance.

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001206642.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 123 of the LDLR protein (p.Ser123Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of familial cholesterolemia (PMID: 19446849, 20045108, 34297352, 36229376; Invitae). ClinVar contains an entry for this variant (Variation ID: 251181). 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 not expected to disrupt LDLR protein function with a negative predictive value of 95%. This variant disrupts the p.Ser123 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 15015036), which suggests that this may be a clinically significant amino acid residue. 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.

#	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

From Color Diagnostics, LLC DBA Color Health, SCV001353457.2

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

Description

This missense variant (also known as p.Ser102Pro in the mature protein) replaces serine with proline at codon 123 of the LDLR protein. This variant occurs at a poorly conserved position 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in two individuals affected with familial hypercholesterolemia (PMID: 19446849, 20045108). One of these individuals carried a pathogenic truncation variant in the same gene that could explain the observed phenotype (PMID: 20045108). This variant has not been identified 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.

#	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: Oct 8, 2024

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