rs41291058

chr1-25563756-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_015627.3(LDLRAP1):c.712C>T(p.Arg238Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0421 in 1,613,906 control chromosomes in the GnomAD database, including 1,745 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R238Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.032 (112 hom., cov: 32)
  • Exomes 𝑓: 0.043 (1633 hom.)
• Consequence: LDLRAP1 NM_015627.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: -0.248

Genes affected

LDLRAP1 (HGNC:18640): (low density lipoprotein receptor adaptor protein 1) The protein encoded by this gene is a cytosolic protein which contains a phosphotyrosine binding (PTD) domain. The PTD domain has been found to interact with the cytoplasmic tail of the LDL receptor. Mutations in this gene lead to LDL receptor malfunction and cause the disorder autosomal recessive hypercholesterolaemia. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032408237).
• BP6: Variant 1-25563756-C-T is Benign according to our data. Variant chr1-25563756-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 296986.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=6, Likely_benign=1}. Variant chr1-25563756-C-T is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0502 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLRAP1	NM_015627.3	c.712C>T	p.Arg238Trp	missense_variant	7/9	ENST00000374338.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLRAP1	ENST00000374338.5	c.712C>T	p.Arg238Trp	missense_variant	7/9	1	NM_015627.3	P1
LDLRAP1	ENST00000484476.5	n.434C>T		non_coding_transcript_exon_variant	2/4	1
LDLRAP1	ENST00000474283.1	n.123C>T		non_coding_transcript_exon_variant	1/3	3
LDLRAP1	ENST00000488127.1	n.1182C>T		non_coding_transcript_exon_variant	6/7	2

Frequencies

GnomAD3 genomes AF: 0.0317 AC: 4830 AN: 152208 Hom.: 112 Cov.: 32

Gnomad AFR AF: 0.00946

Gnomad AMI AF: 0.0592

Gnomad AMR AF: 0.0253

Gnomad ASJ AF: 0.0233

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.0406

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0499

Gnomad OTH AF: 0.0301

GnomAD3 exomes AF: 0.0334 AC: 8370 AN: 250582 Hom.: 196 AF XY: 0.0341 AC XY: 4621 AN XY: 135608

Gnomad AFR exome AF: 0.00842

Gnomad AMR exome AF: 0.0185

Gnomad ASJ exome AF: 0.0251

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00555

Gnomad FIN exome AF: 0.0435

Gnomad NFE exome AF: 0.0529

Gnomad OTH exome AF: 0.0402

GnomAD4 exome AF: 0.0431 AC: 63049 AN: 1461580 Hom.: 1633 Cov.: 33 AF XY: 0.0422 AC XY: 30701 AN XY: 727100

Gnomad4 AFR exome AF: 0.00708

Gnomad4 AMR exome AF: 0.0200

Gnomad4 ASJ exome AF: 0.0245

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00610

Gnomad4 FIN exome AF: 0.0407

Gnomad4 NFE exome AF: 0.0506

Gnomad4 OTH exome AF: 0.0368

GnomAD4 genome AF: 0.0317 AC: 4827 AN: 152326 Hom.: 112 Cov.: 32 AF XY: 0.0294 AC XY: 2188 AN XY: 74498

Gnomad4 AFR AF: 0.00943

Gnomad4 AMR AF: 0.0252

Gnomad4 ASJ AF: 0.0233

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00331

Gnomad4 FIN AF: 0.0406

Gnomad4 NFE AF: 0.0499

Gnomad4 OTH AF: 0.0298

Alfa AF: 0.0389 Hom.: 58

Bravo AF: 0.0301

TwinsUK AF: 0.0550 AC: 204

ALSPAC AF: 0.0537 AC: 207

ESP6500AA AF: 0.0102 AC: 45

ESP6500EA AF: 0.0497 AC: 427

ExAC AF: 0.0355 AC: 4307

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.0491

EpiControl AF: 0.0501

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypercholesterolemia, familial, 4 Uncertain:1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Phosphorus, Inc.	Aug 01, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 472/13006=3.6% -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 25, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Jun 02, 2017

Variant summary: The LDLRAP1 c.712C>T (p.Arg238Trp) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 4281/120134 control chromosomes (112 homozygotes) at a frequency of 0.0356352, which is approximately 45 times the estimated maximal expected allele frequency of a pathogenic LDLRAP1 variant (0.0007906), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Taken together, this variant is classified as benign. -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 05, 2017

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Familial hypercholesterolemia Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.50	D
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.11
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.14
MPC		0.21
ClinPred		0.031	T
GERP RS		0.36
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.094
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs41291058; hg19: chr1-25890247; COSMIC: COSV65473222; COSMIC: COSV65473222;