chr19-11102786-C-T

Position:

chr19-11102786-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_000527.5(LDLR):c.313C>T(p.Pro105Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,613,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense, splice_region

Scores

Splicing: ADA: 0.0002482

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:1

Conservation

PhyloP100: -1.29

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a domain LDL-receptor class A 2 (size 40) in uniprot entity LDLR_HUMAN there are 46 pathogenic changes around while only 6 benign (88%) in NM_000527.5

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08011302).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5 linkuse as main transcript	c.313C>T	p.Pro105Ser	missense_variant, splice_region_variant	3/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 linkuse as main transcript	c.313C>T	p.Pro105Ser	missense_variant, splice_region_variant	3/18	1	NM_000527.5	ENSP00000454071	P3	P01130-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000795

AC:

AN:

251440

Hom.:

AF XY:

0.000110

AC XY:

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000601

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000301

AC:

AN:

1460910

Hom.:

Cov.:

AF XY:

0.0000344

AC XY:

AN XY:

726748

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000375

Gnomad4 NFE exome

AF:

0.0000144

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000471

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000469

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000659

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial hypercholesterolemia

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 12, 2023	This missense variant (also known as p.Pro84Ser in the mature protein) replaces proline with serine at codon 105 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). An experimental functional study using RT-PCR of mRNA from a carrier individual has shown that this variant does not affect normal splicing of the primary transcript (PMID: 9137885). This variant has been reported in one individual and multiple relatives affected with moderate hypercholesterolemia (PMID: 9137885), and in another individual affected with moderate hypercholesterolemia (PMID: 15998910). This variant has been reported in multiple individuals affected with familial hypercholesterolemia as well as in two healthy control individuals (PMID: 26345093). This variant has been identified in 23/282822 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. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 28, 2022	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 105 of the LDLR protein (p.Pro105Ser). This variant is present in population databases (rs13306510, gnomAD 0.07%). This missense change has been observed in individual(s) with hypercholesterolemia and elevated cholesterol (PMID: 9137885). It has also been observed to segregate with disease in related individuals. This variant is also known as Pro84Ser (P84S). ClinVar contains an entry for this variant (Variation ID: 251132). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. -

Hypercholesterolemia, familial, 1

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 13, 2023	This missense variant (also known as p.Pro84Ser in the mature protein) replaces proline with serine at codon 105 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). An experimental functional study using RT-PCR of mRNA from a carrier individual has shown that this variant does not affect normal splicing of the primary transcript (PMID: 9137885). This variant has been reported in one individual and multiple relatives affected with moderate hypercholesterolemia (PMID: 9137885), and in another individual affected with moderate hypercholesterolemia (PMID: 15998910). This variant has been reported in multiple individuals affected with familial hypercholesterolemia as well as in two healthy control individuals (PMID: 26345093). This variant has been identified in 23/282822 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. -
Likely benign, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Nov 12, 2018

Variant summary: LDLR c.313C>T (p.Pro105Ser) results in a non-conservative amino acid change located in the Low-density lipoprotein (LDL) receptor class A repeat region of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.4e-05 in 277426 control chromosomes (gnomAD and publication). This frequency is not significantly higher than expected for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (9.4e-05 vs 0.0013), allowing no conclusion about variant significance. c.313C>T has been reported in the literature in individuals affected with Familial Hypercholesterolemia including a family that suggests lack of cosegregation with disease (Vuorio_1997). 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. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cite the variant as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 02, 2022

Identified in association with hypercholesterolemia; however, in one family, LDL cholesterol levels were not significantly elevated for carriers when compared to non-carriers (Vuorio et al., 1997; Leigh et al., 2008; Alharbi et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.P84S; This variant is associated with the following publications: (PMID: 18700895, 18325082, 26345093, 9137885) -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 27, 2021

The c.313C>T variant (also known as p.P105S), located in coding exon 3 of the LDLR gene, results from a C to T substitution at nucleotide position 313. The amino acid change results in proline to serine at codon 105, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 3, which makes it likely to have some effect on normal mRNA splicing. This alteration has been reported in association with familial hypercholesterolemia (FH) (Vuorio AF et al. Clin Genet, 1997 Mar;51:191-5; Alharbi KK et al. Genome Res, 2005 Jul;15:967-77). This nucleotide and amino acid positions are poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.048

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

0.13

DANN

Benign

0.78

DEOGEN2

Uncertain

0.56

D;.;.;.

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.071

T;T;T;T

M_CAP

Pathogenic

0.44

MetaRNN

Benign

0.080

T;T;T;T

MetaSVM

Benign

-0.76

MutationTaster

Benign

1.0

D;D;D;N;N;N;N

PrimateAI

Benign

0.22

PROVEAN

Benign

-1.3

N;N;D;N

REVEL

Uncertain

0.52

Sift

Benign

0.63

T;T;T;T

Sift4G

Benign

0.73

T;T;T;T

Polyphen

0.0

B;.;.;.

Vest4

0.068

MutPred

0.48

Loss of catalytic residue at P105 (P = 5e-04);Loss of catalytic residue at P105 (P = 5e-04);Loss of catalytic residue at P105 (P = 5e-04);Loss of catalytic residue at P105 (P = 5e-04);

MVP

0.93

MPC

0.21

ClinPred

0.020

GERP RS

-11

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.14

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00025

dbscSNV1_RF

Benign

0.040

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over