NM_000527.5(LDLR):c.1438G>T (p.Ala480Ser) AND Familial hypercholesterolemia

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Nov 29, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV002643933.2

Allele description [Variation Report for NM_000527.5(LDLR):c.1438G>T (p.Ala480Ser)]

NM_000527.5(LDLR):c.1438G>T (p.Ala480Ser)

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.1438G>T (p.Ala480Ser)

HGVS:

NC_000019.10:g.11113614G>T
NG_009060.1:g.29234G>T
NM_000527.5:c.1438G>TMANE SELECT
NM_001195798.2:c.1438G>T
NM_001195799.2:c.1315G>T
NM_001195800.2:c.934G>T
NM_001195803.2:c.1057G>T
NP_000518.1:p.Ala480Ser
NP_000518.1:p.Ala480Ser
NP_001182727.1:p.Ala480Ser
NP_001182728.1:p.Ala439Ser
NP_001182729.1:p.Ala312Ser
NP_001182732.1:p.Ala353Ser
LRG_274t1:c.1438G>T
LRG_274:g.29234G>T
LRG_274p1:p.Ala480Ser
NC_000019.9:g.11224290G>T
NM_000527.4:c.1438G>T

Protein change:

A312S

Molecular consequence:

NM_000527.5:c.1438G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1438G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1315G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.934G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1057G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial hypercholesterolemia (FH)
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
SCV003512063	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Nov 29, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 18701038, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003512063

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Nov 29, 2022)

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

Functional analysis of low-density lipoprotein receptor in homozygous familial hypercholesterolemia patients with novel 1439 C-->T mutation of low-density lipoprotein receptor gene.

Lin J, Wang LY, Liu S, Xia JH, Yong Q, Du LP, Pan XD, Xue H, Chen BS, Jiang ZS.

Chin Med J (Engl). 2008 May 5;121(9):776-81.

PubMed [citation]

PMID:: 18701038

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):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV003512063.2

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

Description

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. 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. This variant disrupts the p.Ala480 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18701038; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant has not been reported in the literature in individuals affected with LDLR-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 480 of the LDLR protein (p.Ala480Ser).

#	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: Feb 28, 2024

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