NM_000527.5(LDLR):c.2101G>A (p.Gly701Ser) AND Familial hypercholesterolemia

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Mar 15, 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:: RCV001181781.8

Allele description [Variation Report for NM_000527.5(LDLR):c.2101G>A (p.Gly701Ser)]

NM_000527.5(LDLR):c.2101G>A (p.Gly701Ser)

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.2101G>A (p.Gly701Ser)

Other names:

NM_000527.5(LDLR):c.2101G>A

HGVS:

NC_000019.10:g.11120483G>A
NG_009060.1:g.36103G>A
NM_000527.5:c.2101G>AMANE SELECT
NM_001195798.2:c.2101G>A
NM_001195799.2:c.1978G>A
NM_001195800.2:c.1597G>A
NM_001195803.2:c.1606+250G>A
NP_000518.1:p.Gly701Ser
NP_000518.1:p.Gly701Ser
NP_001182727.1:p.Gly701Ser
NP_001182728.1:p.Gly660Ser
NP_001182729.1:p.Gly533Ser
LRG_274t1:c.2101G>A
LRG_274:g.36103G>A
LRG_274p1:p.Gly701Ser
NC_000019.9:g.11231159G>A
NM_000527.4:c.2101G>A
c.2101G>A

Protein change:

G533S

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001078; dbSNP: rs368838866

NCBI 1000 Genomes Browser:

rs368838866

Molecular consequence:

NM_001195803.2:c.1606+250G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.2101G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.2101G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1978G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1597G>A - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

unknown functional consequence - Comment(s)

Condition(s)

Name:: Familial hypercholesterolemia
Identifiers:: MONDO: MONDO:0005439; MedGen: C0020445; OMIM: PS143890

Recent activity

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Homo sapiens gonadotropin-releasing hormone receptor (GNRHR), mRNA
Homo sapiens gonadotropin-releasing hormone receptor (GNRHR), mRNA
gi|4504058|ref|NM_000406.1|

Nucleotide
Homo sapiens gonadotropin-releasing hormone receptor, mRNA (cDNA clone MGC:14210...
Homo sapiens gonadotropin-releasing hormone receptor, mRNA (cDNA clone MGC:142106 IMAGE:8322598), complete cds
gi|109731731|gb|BC113546.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001347005	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 15, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 22390909, 25647241, 25741868
SCV001461327	Natera, Inc.	no assertion criteria provided	Uncertain significance (Sep 16, 2020)	germline	clinical testing
SCV002943680	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 26, 2022)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 16250003, 19007590, 19318025, 21310417, 22390909, 25487149, 25647241, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001347005

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 15, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV001461327

Natera, Inc.

no assertion criteria provided

Uncertain significance
(Sep 16, 2020)

germline

clinical testing

SCV002943680

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 26, 2022)

germline

clinical testing

PubMed (8)
[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

Update of the molecular basis of familial hypercholesterolemia in The Netherlands.

Fouchier SW, Kastelein JJ, Defesche JC.

Hum Mutat. 2005 Dec;26(6):550-6.

PubMed [citation]

PMID:: 16250003

See all PubMed Citations (9)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001347005.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This missense variant (also known as p.Gly680Ser in the mature protein) replaces glycine with serine at codon 701 of the LDLR protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown this variant to cause a partial reduction in LDL uptake activity of the LDLR protein (PMID: 25647241). This variant has not shown significant association with increased LDL-C levels, coronary artery disease, or myocardial infarction (PMID: 22390909, 25647241). This variant has been identified in 25/282378 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is no indication that this variant is disease-causing, additional studies are necessary 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

From Natera, Inc., SCV001461327.1

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

#	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, SCV002943680.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 701 of the LDLR protein (p.Gly701Ser). This variant is present in population databases (rs368838866, gnomAD 0.04%). This missense change has been observed in individual(s) with hypercholesterolemia or referred for genetic testing (PMID: 16250003, 19007590, 19318025, 21310417, 22390909, 25487149). ClinVar contains an entry for this variant (Variation ID: 183130). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on LDLR function (PMID: 25647241). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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

Last Updated: Sep 29, 2024

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