NM_000527.5(LDLR):c.761A>C (p.Gln254Pro) AND Familial hypercholesterolemia

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Oct 22, 2023
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:: RCV001190236.9

Allele description [Variation Report for NM_000527.5(LDLR):c.761A>C (p.Gln254Pro)]

NM_000527.5(LDLR):c.761A>C (p.Gln254Pro)

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.761A>C (p.Gln254Pro)

Other names:

FH Reggio; FH Emilia-2

HGVS:

NC_000019.10:g.11106631A>C
NG_009060.1:g.22251A>C
NM_000527.5:c.761A>CMANE SELECT
NM_001195798.2:c.761A>C
NM_001195799.2:c.638A>C
NM_001195800.2:c.314-761A>C
NM_001195803.2:c.380A>C
NP_000518.1:p.Gln254Pro
NP_000518.1:p.Gln254Pro
NP_001182727.1:p.Gln254Pro
NP_001182728.1:p.Gln213Pro
NP_001182732.1:p.Gln127Pro
LRG_274t1:c.761A>C
LRG_274:g.22251A>C
LRG_274p1:p.Gln254Pro
NC_000019.9:g.11217307A>C
NM_000527.4:c.761A>C
NM_000527.5:c.761A>C
P01130:p.Gln254Pro
c.761A>C
p.(Gln254Pro)

Protein change:

Q127P

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000315; UniProtKB: P01130#VAR_062374; dbSNP: rs879254667

NCBI 1000 Genomes Browser:

rs879254667

Molecular consequence:

NM_001195800.2:c.314-761A>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.761A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.761A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.638A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.380A>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
SCV001357683	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 10, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001393260	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 22, 2023)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 10978268, 11754108, 14974088, 19319977, 19446849, 21925044, 25463123, 16250003, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001357683

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Oct 10, 2019)

germline

clinical testing

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

SCV001393260

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 22, 2023)

germline

clinical testing

PubMed (9)
[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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Clinical expression of familial hypercholesterolemia in clusters of mutations of the LDL receptor gene that cause a receptor-defective or receptor-negative phenotype.

Bertolini S, Cantafora A, Averna M, Cortese C, Motti C, Martini S, Pes G, Postiglione A, Stefanutti C, Blotta I, Pisciotta L, Rolleri M, Langheim S, Ghisellini M, Rabbone I, Calandra S.

Arterioscler Thromb Vasc Biol. 2000 Sep;20(9):E41-52.

PubMed [citation]

PMID:: 10978268

See all PubMed Citations (10)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001357683.2

#	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.Gln233Pro in the mature protein and as FH-Reggio Emilia-2) replaces glutamine with proline at codon 254 in the LDLR type A repeat 6 of ligand binding domain of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. A functional study has shown that this variant does not affect protein expression at the cellular surface but reduces LDL binding and internalization activity by 80% compared to wild type protein (PMID: 31578082). This variant has been reported in over ten individuals affected with familial hypercholesterolemia (PMID: 10978268, 11754108, 14974088, 15200491, 16542394, 19446849, 21925044, 22698793, 23375686, 30415195). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as 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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001393260.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 254 of the LDLR protein (p.Gln254Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 10978268, 11754108, 14974088, 19319977, 19446849, 21925044, 25463123). This variant is also known as Q233P and FH Reggio Emilia-2. ClinVar contains an entry for this variant (Variation ID: 251437). 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. This variant disrupts the p.Gln233 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 16250003), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as 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: Oct 13, 2024

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