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NM_000527.5(LDLR):c.1381G>T (p.Gly461Cys) AND Familial hypercholesterolemia

Germline classification:
Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:
Sep 8, 2023
Review status:
criteria provided, conflicting classifications
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:
RCV001804888.5

Allele description [Variation Report for NM_000527.5(LDLR):c.1381G>T (p.Gly461Cys)]

NM_000527.5(LDLR):c.1381G>T (p.Gly461Cys)

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.1381G>T (p.Gly461Cys)
HGVS:
  • NC_000019.10:g.11113557G>T
  • NG_009060.1:g.29177G>T
  • NM_000527.5:c.1381G>TMANE SELECT
  • NM_001195798.2:c.1381G>T
  • NM_001195799.2:c.1258G>T
  • NM_001195800.2:c.877G>T
  • NM_001195803.2:c.1000G>T
  • NP_000518.1:p.Gly461Cys
  • NP_000518.1:p.Gly461Cys
  • NP_001182727.1:p.Gly461Cys
  • NP_001182728.1:p.Gly420Cys
  • NP_001182729.1:p.Gly293Cys
  • NP_001182732.1:p.Gly334Cys
  • LRG_274t1:c.1381G>T
  • LRG_274:g.29177G>T
  • LRG_274p1:p.Gly461Cys
  • NC_000019.9:g.11224233G>T
  • NM_000527.4:c.1381G>T
  • c.1381G>T
Protein change:
G293C
Links:
LDLR-LOVD, British Heart Foundation: LDLR_001418; dbSNP: rs193922568
NCBI 1000 Genomes Browser:
rs193922568
Molecular consequence:
  • NM_000527.5:c.1381G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.1381G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.1258G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.877G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195803.2:c.1000G>T - missense variant - [Sequence Ontology: SO:0001583]
Functional consequence:
no known functional consequence - Comment(s)

Condition(s)

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

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002051933Color Diagnostics, LLC DBA Color Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain significance
(Mar 15, 2021) 		germlineclinical testing

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

SCV003289210Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Likely pathogenic
(Sep 8, 2023) 		germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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

Six novel mutations of the LDL receptor gene in FH kindred of Sicilian and Paraguayan descent.

Cefalù AB, Barraco G, Noto D, Valenti V, Barbagallo CM, Elisir GD, Cuniberti LA, Werba JP, Libra M, Costa S, Gianguzza F, Notarbartolo A, Travali S, Averna MR.

Int J Mol Med. 2006 Mar;17(3):539-46.

PubMed [citation]
PMID:
16465405
See all PubMed Citations (8)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV002051933.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

This missense variant (also known as p.Gly440Cys in the mature protein) replaces glycine with cysteine at codon 461 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with familial hypercholesterolemia from an Italian family (PMID: 16465405) and two Greek individuals affected with familial hypercholesterolemia (PMID: 23815734, 25463123, 27578104). This variant has been identified in 3/282248 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003289210.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

This variant is present in population databases (rs193922568, gnomAD 0.002%). This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 461 of the LDLR protein (p.Gly461Cys). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 16465405, 23375686, 23815734, 35339733). This variant is also known as G440C. ClinVar contains an entry for this variant (Variation ID: 183113). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function. Experimental studies have shown that this missense change does not substantially affect LDLR function (PMID: 25647241). This variant disrupts the p.Gly461 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 35047021), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024