NM_000527.5(LDLR):c.1496C>G (p.Ser499Cys) AND Hypercholesterolemia, familial, 1

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Feb 23, 2024
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV004006466.3

Allele description [Variation Report for NM_000527.5(LDLR):c.1496C>G (p.Ser499Cys)]

NM_000527.5(LDLR):c.1496C>G (p.Ser499Cys)

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.1496C>G (p.Ser499Cys)

Other names:

NM_000527.5(LDLR):c.1496C>G; p.Ser499Cys

HGVS:

NC_000019.10:g.11113672C>G
NG_009060.1:g.29292C>G
NM_000527.5:c.1496C>GMANE SELECT
NM_001195798.2:c.1496C>G
NM_001195799.2:c.1373C>G
NM_001195800.2:c.992C>G
NM_001195803.2:c.1115C>G
NP_000518.1:p.Ser499Cys
NP_001182727.1:p.Ser499Cys
NP_001182728.1:p.Ser458Cys
NP_001182729.1:p.Ser331Cys
NP_001182732.1:p.Ser372Cys
LRG_274t1:c.1496C>G
LRG_274:g.29292C>G
NC_000019.9:g.11224348C>G
NC_000019.9:g.11224348C>G
NM_000527.4:c.1496C>G

Protein change:

S331C

Links:

dbSNP: rs766929574

NCBI 1000 Genomes Browser:

rs766929574

Molecular consequence:

NM_000527.5:c.1496C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1496C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1373C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.992C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1115C>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Hypercholesterolemia, familial, 1
Synonyms:: LDL RECEPTOR DISORDER; Hyperlipoproteinemia Type IIa; HYPER-LOW-DENSITY-LIPOPROTEINEMIA; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007750; MedGen: C0745103; Orphanet: 391665; OMIM: 143890

Recent activity

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carbohydrate sulfotransferase 11 isoform X1 [Phyllostomus discolor]
carbohydrate sulfotransferase 11 isoform X1 [Phyllostomus discolor]
gi|1597519459|ref|XP_028388000.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004822464	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Nov 2, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005375307	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	reviewed by expert panel (ClinGen FH ACMG Specifications v1-2)	Uncertain Significance (Feb 23, 2024)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004822464

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Nov 2, 2023)

germline

clinical testing

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

SCV005375307

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

reviewed by expert panel

(ClinGen FH ACMG Specifications v1-2)

Uncertain Significance
(Feb 23, 2024)

germline

curation

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	108544	not provided	clinical testing, curation

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

Details of each submission

From All of Us Research Program, National Institutes of Health, SCV004822464.1

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

Description

This missense variant replaces serine with cysteine at codon 499 of the LDLR protein. This variant is also known as p.Ser478Cys in the mature protein. This variant alters a conserved serine residue in the LDLR type B repeat 3 of the EGF precursor homology domain in the LDLR protein (a.a. 486 - 528), where pathogenic missense variants are found enriched (ClinVar-LDLR). 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 an individual affected with familial hypercholesterolemia (Color internal data). This variant has been identified in 3/251458 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Ser499Pro, is reported to cause disease (ClinVar variation ID: 251870), indicating that serine at this position is important for LDLR protein function. 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	108544	not provided	not provided		1	not provided	not provided	not provided

From ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, SCV005375307.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

The NM_000527.5(LDLR):c.1496C>G (p.Ser499Cys) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024. The supporting evidence is as follows: PM2: PopMax MAF = 0.00003764 (0.004%) in European (Finnish) exomes (gnomAD v4.0.0). PP3: REVEL = 0.811.

#	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 26, 2024

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