19-11131631-G-C

Variant names:

• chr19-11131631-G-C
• rs2738464
• NM_000527.5:c.*315G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000527.5(LDLR):​c.*315G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.838 in 624,540 control chromosomes in the GnomAD database, including 221,183 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.80 (49823 hom., cov: 29)
  • Exomes 𝑓: 0.85 (171360 hom.)
• Consequence: LDLR NM_000527.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.261
• Publications: 51 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]

SPC24 (HGNC:26913): (SPC24 component of NDC80 kinetochore complex) Predicted to be involved in cell division. Located in nucleolus and nucleoplasm. Part of Ndc80 complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 19-11131631-G-C is Benign according to our data. Variant chr19-11131631-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 328058.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.876 is higher than 0.05.

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.*315G>C		3_prime_UTR	Exon 18 of 18	NP_000518.1
	LDLR	NM_001195798.2		c.*315G>C		3_prime_UTR	Exon 18 of 18	NP_001182727.1
	LDLR	NM_001195799.2		c.*315G>C		3_prime_UTR	Exon 17 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.*315G>C		3_prime_UTR	Exon 18 of 18	ENSP00000454071.1
	LDLR	ENST00000252444.10	TSL:1	c.*315G>C		3_prime_UTR	Exon 18 of 18	ENSP00000252444.6
	LDLR	ENST00000558013.5	TSL:1	c.*315G>C		3_prime_UTR	Exon 18 of 18	ENSP00000453346.1

Frequencies

GnomAD3 genomes AF: 0.804 AC: 122048 AN: 151760 Hom.: 49799 Cov.: 29

Gnomad AFR AF: 0.658

Gnomad AMI AF: 0.907

Gnomad AMR AF: 0.817

Gnomad ASJ AF: 0.838

Gnomad EAS AF: 0.713

Gnomad SAS AF: 0.796

Gnomad FIN AF: 0.881

Gnomad MID AF: 0.851

Gnomad NFE AF: 0.881

Gnomad OTH AF: 0.833

GnomAD2 exomes AF: 0.819 AC: 59038 AN: 72086 AF XY: 0.823

Gnomad AFR exome AF: 0.653

Gnomad AMR exome AF: 0.816

Gnomad ASJ exome AF: 0.838

Gnomad EAS exome AF: 0.725

Gnomad FIN exome AF: 0.880

Gnomad NFE exome AF: 0.881

Gnomad OTH exome AF: 0.849

GnomAD4 exome AF: 0.849 AC: 401273 AN: 472662 Hom.: 171360 Cov.: 2 AF XY: 0.848 AC XY: 213684 AN XY: 251960

African (AFR) AF: 0.659 AC: 8569 AN: 13010

American (AMR) AF: 0.818 AC: 18344 AN: 22424

Ashkenazi Jewish (ASJ) AF: 0.851 AC: 12676 AN: 14888

East Asian (EAS) AF: 0.696 AC: 21958 AN: 31564

South Asian (SAS) AF: 0.795 AC: 38514 AN: 48472

European-Finnish (FIN) AF: 0.882 AC: 26632 AN: 30178

Middle Eastern (MID) AF: 0.847 AC: 1917 AN: 2262

European-Non Finnish (NFE) AF: 0.883 AC: 249695 AN: 282786

Other (OTH) AF: 0.848 AC: 22968 AN: 27078

GnomAD4 genome AF: 0.804 AC: 122126 AN: 151878 Hom.: 49823 Cov.: 29 AF XY: 0.804 AC XY: 59725 AN XY: 74248

African (AFR) AF: 0.658 AC: 27208 AN: 41348

American (AMR) AF: 0.818 AC: 12446 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.838 AC: 2909 AN: 3472

East Asian (EAS) AF: 0.712 AC: 3677 AN: 5162

South Asian (SAS) AF: 0.796 AC: 3819 AN: 4798

European-Finnish (FIN) AF: 0.881 AC: 9320 AN: 10580

Middle Eastern (MID) AF: 0.847 AC: 249 AN: 294

European-Non Finnish (NFE) AF: 0.881 AC: 59923 AN: 67984

Other (OTH) AF: 0.831 AC: 1748 AN: 2104

Alfa AF: 0.846 Hom.: 7424

Bravo AF: 0.793

Asia WGS AF: 0.737 AC: 2563 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Jun 11, 2018

Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Due to the increased occurrence of the mutation (>= 5%) and the current estimates of databases (LOVD 3), this variant is classified as likely benign.

Familial hypercholesterolemia Benign:2

Jun 30, 2022

GENinCode PLC

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.53
DANN	Benign	0.39
PhyloP100		-0.26
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs2738464; hg19: chr19-11242307; COSMIC: COSV52943041; COSMIC: COSV52943041;