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

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Mar 13, 2017
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:: RCV000844739.4

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]

Observations:

Condition(s)

Name:: Homozygous familial hypercholesterolemia
Synonyms:: Familial hypercholesterolemia - homozygous
Identifiers:: MONDO: MONDO:0018328; MedGen: C0342881

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000712914	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely pathogenic (Mar 13, 2017)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 16542394, 15200491, 21925044, 14974088, 23510778, 23375686, 22698793, 11754108, 10978268, 19446849, 24033266

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000712914

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Likely pathogenic
(Mar 13, 2017)

germline

clinical testing

PubMed (11)
[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	not provided	1	1	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular genetic analysis of 1053 Danish individuals with clinical signs of familial hypercholesterolemia.

Brusgaard K, Jordan P, Hansen H, Hansen AB, Hørder M.

Clin Genet. 2006 Mar;69(3):277-83.

PubMed [citation]

PMID:: 16542394

FH clinical phenotype in Greek patients with LDL-R defective vs. negative mutations.

Dedoussis GV, Skoumas J, Pitsavos C, Choumerianou DM, Genschel J, Schmidt H, Stefanadis C.

Eur J Clin Invest. 2004 Jun;34(6):402-9.

PubMed [citation]

PMID:: 15200491

See all PubMed Citations (11)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000712914.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (11)

Description

The p.Gln254Pro variant in LDLR has been reported in the heterozygous state in 9 individuals with familial hypercholesterolemia, as well as one homozygote (Bert olini 2000, Dedoussis 2004, Brusgaard 2006, Diakou 2011, Tichy 2012, Bertolini 2 013. In addition, this variant has been reported in a consanguineous family alon g with a second hypercholesterolemia variant (LDLRAP1 p.Gly136X). In this family , disease severity correlated with the various combinations of heterozygosity or homozygosity for the two variants (Soufi 2013). The p.Gln254Pro variant has als o been reported in ClinVar (Variation ID 251437) and was absent from large popul ation studies. In summary, although additional studies are required to fully est ablish its clinical significance, the p.Gln254Pro variant is likely pathogenic.

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

Last Updated: Oct 13, 2024

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