NM_000527.5(LDLR):c.621C>T (p.Gly207=) AND Cardiovascular phenotype

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 23, 2021
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:: RCV002362561.2

Allele description [Variation Report for NM_000527.5(LDLR):c.621C>T (p.Gly207=)]

NM_000527.5(LDLR):c.621C>T (p.Gly207=)

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.621C>T (p.Gly207=)

Other names:

G186G; NP_000518.1:p.Gly207Gly=; p.Gly207=

HGVS:

NC_000019.10:g.11105527C>T
NG_009060.1:g.21147C>T
NM_000527.5:c.621C>TMANE SELECT
NM_001195798.2:c.621C>T
NM_001195799.2:c.498C>T
NM_001195800.2:c.314-1865C>T
NM_001195803.2:c.314-1038C>T
NP_000518.1:p.Gly207=
NP_000518.1:p.Gly207=
NP_001182727.1:p.Gly207=
NP_001182728.1:p.Gly166=
LRG_274t1:c.621C>T
LRG_274:g.21147C>T
LRG_274p1:p.Gly207=
NC_000019.9:g.11216203C>T
NM_000527.4:c.621C>T
c.621C>T

Protein change:

GLY186GLY

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001228; OMIM: 606945.0066; dbSNP: rs121908044

Molecular consequence:

NM_001195800.2:c.314-1865C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.314-1038C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.621C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001195798.2:c.621C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001195799.2:c.498C>T - synonymous variant - [Sequence Ontology: SO:0001819]

Condition(s)

Name:: Cardiovascular phenotype
Identifiers:: MedGen: CN230736

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002659775	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Dec 23, 2021)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 18400033, 21382890, 21475731, 22390909, 25412742, 27784735, 28104544, 32977124, 33740630, 34037665 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002659775

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Dec 23, 2021)

germline

clinical testing

PubMed (10)
[See all records that cite these PMIDs]

Citation Link

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

Silent exonic mutations in the low-density lipoprotein receptor gene that cause familial hypercholesterolemia by affecting mRNA splicing.

Defesche JC, Schuurman EJ, Klaaijsen LN, Khoo KL, Wiegman A, Stalenhoef AF.

Clin Genet. 2008 Jun;73(6):573-8. doi: 10.1111/j.1399-0004.2008.00999.x. Epub 2008 Apr 8.

PubMed [citation]

PMID:: 18400033

Molecular basis of autosomal dominant hypercholesterolemia: assessment in a large cohort of hypercholesterolemic children.

van der Graaf A, Avis HJ, Kusters DM, Vissers MN, Hutten BA, Defesche JC, Huijgen R, Fouchier SW, Wijburg FA, Kastelein JJ, Wiegman A.

Circulation. 2011 Mar 22;123(11):1167-73. doi: 10.1161/CIRCULATIONAHA.110.979450. Epub 2011 Mar 7.

PubMed [citation]

PMID:: 21382890

See all PubMed Citations (10)

Details of each submission

From Ambry Genetics, SCV002659775.2

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

Description

The c.621C>T pathogenic mutation (also known as p.G207G), located in coding exon 4, results from a C to T substitution at nucleotide position 621 of the LDLR gene. This nucleotide substitution does not change the amino acid at codon 207. This mutation has been reported in several familial hypercholesterolemia cohorts, and in one of the studies, the average LDL-C level in family members positive for the mutation was elevated compared with relatives who did not carry the alteration (Defesche JC et al. Clin. Genet. 2008;73:573-8; Kusters DM et al. Neth Heart J. 2011;19:175-182; Sánchez-Hernández RM et al. Circ Cardiovasc Genet. 2016;9:504-510; Durst R et al. Atherosclerosis. 2017;257:55-63). In addition, this mutation has been identified in the homozygous state in two unrelated individuals with LDL-C levels indicative of homozygous familial hypercholesterolemia, both of whom suffered myocardial infarction at a young age (Defesche JC et al. Clin. Genet. 2008;73:573-8). RNA studies indicate that the variant creates a cryptic donor splice site in coding exon 4 and results in the in-frame deletion of 25 amino acids in LDL type A repeat 5, which is important for ligand binding (Defesche JC et al. Clin. Genet. 2008;73:573-8). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

#	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: Apr 12, 2026

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