19-11107469-G-T

Variant names:

• chr19-11107469-G-T
• rs879254711
• NM_000527.5:c.895G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5 (LDLR): c.895G>T (p.Ala299Ser) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4) 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: This variant is absent in gnomAD (gnomAD v2.1.1).PP4 Met: This variant meets PM2 and is identified in 1 index case who met clinical criteria for FH after alternative causes for high cholesterol were excluded (Lipid Clinic, Fundación Jiménez Díaz, Madrid, Spain, PMID 19318025).PP3 not Met: REVEL score = 0.519, 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 = -2.99, authentic donor = 8.14. 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: Functional data is not available.PM5 not met: There is one other variant in the same codon: LDLR: NM_000527:c.895G>A (p.Ala299Thr) is classified as Uncertain significance - insufficient evidence by these guidelines. Therefore PM5 is not met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585180/MONDO:0007750/013

• Frequency: Genomes: not found (cov: 32)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:3 B:1
• Conservation: PhyloP100: 0.794
• Publications: 10 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 3 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.895G>T	p.Ala299Ser	missense_variant	Exon 6 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.895G>T	p.Ala299Ser	missense_variant	Exon 6 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:3 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

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

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Mar 01, 2016

Fundacion Hipercolesterolemia Familiar

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Feb 10, 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.895G>T (p.Ala299Ser) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4) 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: This variant is absent in gnomAD (gnomAD v2.1.1). PP4 Met: This variant meets PM2 and is identified in 1 index case who met clinical criteria for FH after alternative causes for high cholesterol were excluded (Lipid Clinic, Fundación Jiménez Díaz, Madrid, Spain, PMID 19318025). PP3 not Met: REVEL score = 0.519, 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 = -2.99, authentic donor = 8.14. 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: Functional data is not available. PM5 not met: There is one other variant in the same codon: LDLR: NM_000527:c.895G>A (p.Ala299Thr) is classified as Uncertain significance - insufficient evidence by these guidelines. Therefore PM5 is not met. -

Familial hypercholesterolemia Pathogenic:1

Aug 16, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.Ala299 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 21990180), which suggests that this may be a clinically significant amino acid residue. 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 not expected to disrupt LDLR protein function. ClinVar contains an entry for this variant (Variation ID: 251508). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 18096825, 19318025). 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 299 of the LDLR protein (p.Ala299Ser). -

not specified Uncertain:1

Mar 31, 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.895G>T (p.Ala299Ser) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251388 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.895G>T has been reported in the literature in individual(s) affected with Familial Hypercholesterolemia, however not all the information was availalbe at this curation (Alonso_2009). 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 publication has been ascertained in the context of this evaluation (PMID: 19318025). ClinVar contains an entry for this variant (Variation ID: 251508). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Cardiovascular phenotype Uncertain:1

Dec 18, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.895G>T (p.A299S) alteration is located in exon 6 (coding exon 6) of the LDLR gene. This alteration results from a G to T substitution at nucleotide position 895, causing the alanine (A) at amino acid position 299 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	3.4
DANN	Benign	0.63
DEOGEN2	Uncertain	0.45	T;.;.;.;.;.
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.71	T;T;T;T;T;T
M_CAP	Pathogenic	0.42	D
MetaRNN	Uncertain	0.50	T;T;T;T;T;T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	0.080	N;.;.;.;.;N
PhyloP100		0.79
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.35	N;N;N;N;N;N
REVEL	Uncertain	0.52
Sift	Benign	0.51	T;T;T;T;T;T
Sift4G	Benign	0.73	T;T;T;T;T;T
Polyphen		0.0040	B;.;.;.;.;.
Vest4		0.38
MutPred		0.59		Gain of disorder (P = 0.0114);Gain of disorder (P = 0.0114);.;.;.;Gain of disorder (P = 0.0114);
MVP		1.0
MPC		0.23
ClinPred		0.20	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.21
gMVP		0.75
Mutation Taster		=4/96	disease causing (ClinVar)

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: rs879254711; hg19: chr19-11218145;