rs1060499931

Variant names:

• chr19-11105416-C-A
• rs1060499931
• NM_000527.5:c.510C>A

Your query was ambiguous. Multiple possible variants found:

• chr19-11105416-C-A
• chr19-11105416-C-G
• chr19-11105416-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM1 PS4_Supporting PP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.510C>A (p.Asp170Glu) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM1, PM2, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 9 March 2025. The supporting evidence is as follows:PM2: PopMax MAF = 0.00002664 (0.002664%) in African/African American exomes (gnomAD v4.1.0).PM1: Variant meets PM2 and is missense in exon 4.PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 2 unrelated index cases who fulfill Simon Broome criteria for possible FH (1 case from Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Czech Republic; 1 case meeting Simon Broome criteria for possible FH in PMID 27824480 (Gabčová et al., 2017)). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16609804/MONDO:0007750/013

• Frequency: Genomes: not found (cov: 33)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 U:3
• Conservation: PhyloP100: -0.770

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.510C>A	p.Asp170Glu	missense_variant	Exon 4 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.510C>A	p.Asp170Glu	missense_variant	Exon 4 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:3

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:2 Uncertain:1

Mar 20, 2017

Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 09, 2025

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000527.5(LDLR):c.510C>A (p.Asp170Glu) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM1, PM2, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 9 March 2025. The supporting evidence is as follows: PM2: PopMax MAF = 0.00002664 (0.002664%) in African/African American exomes (gnomAD v4.1.0). PM1: Variant meets PM2 and is missense in exon 4. PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 2 unrelated index cases who fulfill Simon Broome criteria for possible FH (1 case from Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Czech Republic; 1 case meeting Simon Broome criteria for possible FH in PMID 27824480 (Gabcová et al., 2017)). -

May 30, 2024

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.Asp149Glu in the mature protein) replaces aspartic acid with glutamic acid at codon 170 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 been reported in 2 individuals affected with familial hypercholesterolemia in one family (PMID: 27824480). This variant has not been identified 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. -

Familial hypercholesterolemia Uncertain:2

Nov 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 170 of the LDLR protein (p.Asp170Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of familial hypercholesterolemia (PMID: 27824480, 36229376). ClinVar contains an entry for this variant (Variation ID: 403662). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The glutamic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

May 12, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces aspartic acid with glutamic acid at codon 170 of the LDLR protein. This variant is also known as p.Asp149Glu in the mature protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with familial hypercholesterolemia in one family (PMID: 27824480). This variant has not been identified 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	0.0059	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	0.080
DANN	Benign	0.97
DEOGEN2	Uncertain	0.66	D;.;.;.
Eigen	Benign	-0.97
Eigen_PC	Benign	-1.1
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.75	T;T;T;T
M_CAP	Pathogenic	0.36	D
MetaRNN	Uncertain	0.57	D;D;D;D
MetaSVM	Uncertain	0.20	D
MutationAssessor	Benign	1.1	L;.;.;L
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-2.0	N;N;N;N
REVEL	Benign	0.29
Sift	Benign	0.36	T;T;T;T
Sift4G	Benign	0.22	T;T;T;T
Polyphen		0.11	B;.;.;.
Vest4		0.16
MutPred		0.69		Loss of disorder (P = 0.2541);Loss of disorder (P = 0.2541);.;Loss of disorder (P = 0.2541);
MVP		1.0
MPC		0.31
ClinPred		0.59	D
GERP RS		-4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.49
gMVP		0.95

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

Publications

LitVar

Other links and lift over

dbSNP: rs1060499931; hg19: chr19-11216092;