NM_000527.5:c.2113G>T

Variant names:

• chr19-11120495-G-T
• rs193922570
• NM_000527.5:c.2113G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP4 PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000527.5 (LDLR): c.2113G>T (p.Ala705Ser) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4, PS4_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2 Met: PopMAX MAF = 0.00004 in European (Non-Finnish) population in gnomAD (gnomAD v2.1.1).PP4 Met: This variant meets PM2 and is identified in >1 index cases who met clinical criteria for FH after alternative causes for high cholesterol were excluded.PS4_Supporting Met: Variant meets PM2 and is identified in 2 unrelated index cases who fulfil DLCN criteria or Simon Broome criteria for FH from 2 different labs: 1 case met DLCN criteria from Robarts Research Institute, Canada; 1 case met Simon Broome criteria from Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Royal Free and University College London Medical School, London, UK, PMID 17142622.PP3 not met: REVEL score = 0.673, which is below the threshold of 0.75. Functional data on splicing is not available, in silico splicing prediction is required. Variant is exonic and at least 50bp downstream from acceptor site and creates GT. MES scores: de novo donor = -6.49, authentic donor = 7.81. De novo score is negative and not used, therefore the variant is not predicted to alter splicing.BP4 not applicable: REVEL score is > 0.5, therefore BP4 is not applicable.PS3 not met: There is no functional experiment reported for this variant. PM5 not met: There is one other variant in the same codon: LDLR: NM_000527:c.2113G>C (p.Ala705Pro) is classified as Uncertain significance - insufficient evidence by these guidelines. Therefore PM5 is not met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585777/MONDO:0007750/013

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:5 B:1
• Conservation: PhyloP100: 6.83
• Publications: 9 publications found

Genes affected

LDLR (HGNC:6547): (low density lipoprotein receptor) The low density lipoprotein receptor (LDLR) gene family consists of cell surface proteins involved in receptor-mediated endocytosis of specific ligands. The encoded protein is normally bound at the cell membrane, where it binds low density lipoprotein/cholesterol and is taken into the cell. Lysosomes release the cholesterol, which is made available for repression of microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting step in cholesterol synthesis. At the same time, a reciprocal stimulation of cholesterol ester synthesis takes place. Mutations in this gene cause the autosomal dominant disorder, familial hypercholesterolemia. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2022]

LDLR Gene-Disease associations (from GenCC):

• hypercholesterolemia, familial, 1

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000527.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	NM_000527.5	MANE Select	c.2113G>T	p.Ala705Ser	missense	Exon 14 of 18	NP_000518.1
	LDLR	NM_001195798.2		c.2113G>T	p.Ala705Ser	missense	Exon 14 of 18	NP_001182727.1
	LDLR	NM_001195799.2		c.1990G>T	p.Ala664Ser	missense	Exon 13 of 17	NP_001182728.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.2113G>T	p.Ala705Ser	missense	Exon 14 of 18	ENSP00000454071.1
	LDLR	ENST00000252444.10	TSL:1	c.2371G>T	p.Ala791Ser	missense	Exon 14 of 18	ENSP00000252444.6
	LDLR	ENST00000558013.5	TSL:1	c.2113G>T	p.Ala705Ser	missense	Exon 14 of 18	ENSP00000453346.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 250870 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000226 AC: 33 AN: 1461344 Hom.: 0 Cov.: 35 AF XY: 0.0000275 AC XY: 20 AN XY: 727002

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52884

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000279 AC: 31 AN: 1112012

Other (OTH) AF: 0.0000331 AC: 2 AN: 60388

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.00000378

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:5 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:1 Uncertain:3 Benign:1

Aug 15, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant (also known as p.Ala684Ser in the mature protein) replaces alanine with serine at codon 705 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 individuals affected with familial hypercholesterolemia (PMID: 15556093, 18325082) and in an individual affected with hyperlipidemia (PMID: 33303402). This variant has been identified in 5/250870 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.

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: literature only

Sep 08, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Feb 25, 2022

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000527.5 (LDLR): c.2113G>T (p.Ala705Ser) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4, PS4_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 Met: PopMAX MAF = 0.00004 in European (Non-Finnish) population in gnomAD (gnomAD v2.1.1). PP4 Met: This variant meets PM2 and is identified in >1 index cases who met clinical criteria for FH after alternative causes for high cholesterol were excluded. PS4_Supporting Met: Variant meets PM2 and is identified in 2 unrelated index cases who fulfil DLCN criteria or Simon Broome criteria for FH from 2 different labs: 1 case met DLCN criteria from Robarts Research Institute, Canada; 1 case met Simon Broome criteria from Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Royal Free and University College London Medical School, London, UK, PMID 17142622. PP3 not met: REVEL score = 0.673, which is below the threshold of 0.75. Functional data on splicing is not available, in silico splicing prediction is required. Variant is exonic and at least 50bp downstream from acceptor site and creates GT. MES scores: de novo donor = -6.49, authentic donor = 7.81. De novo score is negative and not used, therefore the variant is not predicted to alter splicing. BP4 not applicable: REVEL score is > 0.5, therefore BP4 is not applicable. PS3 not met: There is no functional experiment reported for this variant. PM5 not met: There is one other variant in the same codon: LDLR: NM_000527:c.2113G>C (p.Ala705Pro) is classified as Uncertain significance - insufficient evidence by these guidelines. Therefore PM5 is not met.

Familial hypercholesterolemia Pathogenic:1

Sep 08, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 705 of the LDLR protein (p.Ala705Ser). This missense change has been observed in individual(s) with combined hyperlipidemia and/or familial hypercholesterolemia (PMID: 15556093, 33303402). ClinVar contains an entry for this variant (Variation ID: 252224). This variant is also known as A684S. This variant is present in population databases (rs193922570, gnomAD 0.004%). 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.Ala705 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11810272, 18325082, 21382890, 22095935, 23375686, 25412742). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.

not specified Uncertain:1

Jun 06, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: LDLR c.2113G>T (p.Ala705Ser) results in a conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. 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. The variant allele was found at a frequency of 2e-05 in 250870 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2113G>T has been reported in the literature in the heterozygous state in at least 1 individual affected with Familial Hypercholesterolemia (example, Gill_2021, Guerin_2023, Leigh_2008). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33303402, 37607748, 18325082). ClinVar contains an entry for this variant (Variation ID: 252224). Based on the evidence outlined above, the variant was classified as uncertain significance.

Cardiovascular phenotype Uncertain:1

Jul 18, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A705S variant (also known as c.2113G>T), located in coding exon 14 of the LDLR gene, results from a G to T substitution at nucleotide position 2113. The alanine at codon 705 is replaced by serine, an amino acid with similar properties. This variant (also referred to as p.A684S) was reported in individual(s) with features consistent with familial hypercholesterolemia (Humphries SE et al. J Med Genet, 2006 Dec;43:943-9; Sozen M et al. Atheroscler Suppl, 2004 Dec;5:7-11; Whittall RA et al. Ann Clin Biochem, 2010 Jan;47:44-55; Gill PK et al. J Clin Lipidol, 2021 Nov;15:79-87). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.65	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Benign	1.5	L
PhyloP100		6.8
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.99	N
REVEL	Pathogenic	0.67
Sift	Benign	0.18	T
Sift4G	Benign	0.55	T
Polyphen		0.38	B
Vest4		0.19
MutPred		0.80		Gain of disorder (P = 0.029)
MVP		1.0
MPC		0.62
ClinPred		0.78	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.42
gMVP		0.80
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs193922570; hg19: chr19-11231171;