NM_000527.5(LDLR):c.2023G>A (p.Gly675Ser) AND Familial hypercholesterolemia

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 31, 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:: RCV000810496.13

Allele description [Variation Report for NM_000527.5(LDLR):c.2023G>A (p.Gly675Ser)]

NM_000527.5(LDLR):c.2023G>A (p.Gly675Ser)

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.2023G>A (p.Gly675Ser)

Other names:

NM_000527.5(LDLR):c.2023G>A

HGVS:

NC_000019.10:g.11120405G>A
NG_009060.1:g.36025G>A
NM_000527.5:c.2023G>AMANE SELECT
NM_001195798.2:c.2023G>A
NM_001195799.2:c.1900G>A
NM_001195800.2:c.1519G>A
NM_001195803.2:c.1606+172G>A
NP_000518.1:p.Gly675Ser
NP_000518.1:p.Gly675Ser
NP_001182727.1:p.Gly675Ser
NP_001182728.1:p.Gly634Ser
NP_001182729.1:p.Gly507Ser
LRG_274t1:c.2023G>A
LRG_274:g.36025G>A
LRG_274p1:p.Gly675Ser
NC_000019.9:g.11231081G>A
NM_000527.4:c.2023G>A
c.2023G>A

Protein change:

G507S

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000579; dbSNP: rs770744861

NCBI 1000 Genomes Browser:

rs770744861

Molecular consequence:

NM_001195803.2:c.1606+172G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.2023G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.2023G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1900G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1519G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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ydgK [Bacillus subtilis subsp. subtilis str. 168]
ydgK [Bacillus subtilis subsp. subtilis str. 168]
Gene ID:938060

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000950699	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 27, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 11754108, 22698793, 27824480, 28492532
SCV001360361	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 31, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 11754108, 21310417, 22698793, 27824480, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000950699

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 27, 2021)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV001360361

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jan 31, 2023)

germline

clinical testing

PubMed (5)
[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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Spectrum of low density lipoprotein receptor mutations in Czech hypercholesterolemic patients.

Kuhrová V, Francová H, Zapletalová P, Freiberger T, Fajkusová L, Hrabincová E, Slováĉková R, Kozák L, Slováková R.

Hum Mutat. 2002 Jan;19(1):80.

PubMed [citation]

PMID:: 11754108

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000950699.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces glycine with serine at codon 675 of the LDLR protein (p.Gly675Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs770744861, ExAC 0.002%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 11754108, 22698793, 27824480). This variant is also known as p.Gly654Ser. ClinVar contains an entry for this variant (Variation ID: 252173). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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, SCV001360361.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This missense variant (also known as p.Gly654Ser in the mature protein) replaces glycine with serine at codon 675 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 11754108, 21310417, 22698793, 27824480). This variant has been identified in 1/249908 chromosomes 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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