NM_000527.5(LDLR):c.1777G>T (p.Gly593Cys) AND Familial hypercholesterolemia

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Jul 11, 2022
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:: RCV001341649.14

Allele description [Variation Report for NM_000527.5(LDLR):c.1777G>T (p.Gly593Cys)]

NM_000527.5(LDLR):c.1777G>T (p.Gly593Cys)

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.1777G>T (p.Gly593Cys)

HGVS:

NC_000019.10:g.11116930G>T
NG_009060.1:g.32550G>T
NM_000527.5:c.1777G>TMANE SELECT
NM_001195798.2:c.1777G>T
NM_001195799.2:c.1654G>T
NM_001195800.2:c.1273G>T
NM_001195803.2:c.1396G>T
NP_000518.1:p.Gly593Cys
NP_001182727.1:p.Gly593Cys
NP_001182728.1:p.Gly552Cys
NP_001182729.1:p.Gly425Cys
NP_001182732.1:p.Gly466Cys
LRG_274t1:c.1777G>T
LRG_274:g.32550G>T
NC_000019.9:g.11227606G>T
NM_000527.4:c.1777G>T

Protein change:

G425C

Links:

dbSNP: rs544456198

NCBI 1000 Genomes Browser:

rs544456198

Molecular consequence:

NM_000527.5:c.1777G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1777G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1654G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1273G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1396G>T - 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
SCV001535531	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 11, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001735431	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 16, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002086849	Natera, Inc.	no assertion criteria provided	Uncertain significance (May 19, 2021)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001535531

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 11, 2022)

germline

clinical testing

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

SCV001735431

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Feb 16, 2022)

germline

clinical testing

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

SCV002086849

Natera, Inc.

no assertion criteria provided

Uncertain significance
(May 19, 2021)

germline

clinical testing

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

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

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001535531.5

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

Description

Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 1038354). This variant has not been reported in the literature in individuals affected with LDLR-related conditions. This variant is present in population databases (rs544456198, gnomAD 0.006%). This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 593 of the LDLR protein (p.Gly593Cys). 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, SCV001735431.2

#	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.Gly572Cys in the mature protein) replaces glycine with cysteine at codon 593 of the LDLR protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with familial hypercholesterolemia in the literature. This variant has been identified in 2/251486 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

From Natera, Inc., SCV002086849.1

#	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

Last Updated: Sep 29, 2024

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