NM_000527.5(LDLR):c.2171C>T (p.Thr724Ile) AND Familial hypercholesterolemia

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Dec 18, 2021
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:: RCV001804978.5

Allele description [Variation Report for NM_000527.5(LDLR):c.2171C>T (p.Thr724Ile)]

NM_000527.5(LDLR):c.2171C>T (p.Thr724Ile)

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.2171C>T (p.Thr724Ile)

HGVS:

NC_000019.10:g.11123204C>T
NG_009060.1:g.38824C>T
NM_000527.5:c.2171C>TMANE SELECT
NM_001195798.2:c.2171C>T
NM_001195799.2:c.2048C>T
NM_001195800.2:c.1667C>T
NM_001195803.2:c.1637C>T
NP_000518.1:p.Thr724Ile
NP_001182727.1:p.Thr724Ile
NP_001182728.1:p.Thr683Ile
NP_001182729.1:p.Thr556Ile
NP_001182732.1:p.Thr546Ile
LRG_274t1:c.2171C>T
LRG_274:g.38824C>T
NC_000019.9:g.11233880C>T
NM_000527.4:c.2171C>T
c.2171C>T

Protein change:

T546I

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001612; dbSNP: rs879255154

NCBI 1000 Genomes Browser:

rs879255154

Molecular consequence:

NM_000527.5:c.2171C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.2171C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.2048C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1667C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1637C>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
SCV002053091	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Apr 13, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002175403	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 18, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23375686, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002053091

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Apr 13, 2021)

germline

clinical testing

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

SCV002175403

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 18, 2021)

germline

clinical testing

PubMed (2)
[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

Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy.

Bertolini S, Pisciotta L, Rabacchi C, Cefalù AB, Noto D, Fasano T, Signori A, Fresa R, Averna M, Calandra S.

Atherosclerosis. 2013 Apr;227(2):342-8. doi: 10.1016/j.atherosclerosis.2013.01.007. Epub 2013 Jan 19.

PubMed [citation]

PMID:: 23375686

See all PubMed Citations (3)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV002053091.1

#	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.Thr703Ile in the mature protein) replaces threonine with isoleucine at codon 724 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 2/251224 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 Labcorp Genetics (formerly Invitae), Labcorp, SCV002175403.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 724 of the LDLR protein (p.Thr724Ile). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 23375686). ClinVar contains an entry for this variant (Variation ID: 252246). 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 tolerated. 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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