rs121908326

chr1-25563142-C-Achr1-25563142-C-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM5 BP4_Moderate BS2

The NM_015627.3(LDLRAP1):c.605C>A(p.Ser202Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000839 in 1,613,942 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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. S202H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00075 (6 hom.)
• Consequence: LDLRAP1 NM_015627.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:3 B:2
• Conservation: PhyloP100: 0.592

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 Likely_benign. Variant got -4 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-25563141-T-CC is described in ClinVar as [Pathogenic]. Clinvar id is 1751270.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.15271023).
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLRAP1	NM_015627.3	c.605C>A	p.Ser202Tyr	missense_variant	6/9	ENST00000374338.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLRAP1	ENST00000374338.5	c.605C>A	p.Ser202Tyr	missense_variant	6/9	1	NM_015627.3	P1
LDLRAP1	ENST00000484476.5	n.327C>A		non_coding_transcript_exon_variant	1/4	1
LDLRAP1	ENST00000488127.1	n.1075C>A		non_coding_transcript_exon_variant	5/7	2

Frequencies

GnomAD3 genomes AF: 0.00164 AC: 249 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00316

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000882

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00115 AC: 289 AN: 250500 Hom.: 2 AF XY: 0.00116 AC XY: 157 AN XY: 135524

Gnomad AFR exome AF: 0.00267

Gnomad AMR exome AF: 0.00200

Gnomad ASJ exome AF: 0.00289

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000589

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00101

Gnomad OTH exome AF: 0.00262

GnomAD4 exome AF: 0.000755 AC: 1103 AN: 1461688 Hom.: 6 Cov.: 34 AF XY: 0.000822 AC XY: 598 AN XY: 727188

Gnomad4 AFR exome AF: 0.00299

Gnomad4 AMR exome AF: 0.00228

Gnomad4 ASJ exome AF: 0.00306

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000626

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000542

Gnomad4 OTH exome AF: 0.00174

GnomAD4 genome AF: 0.00165 AC: 251 AN: 152254 Hom.: 0 Cov.: 32 AF XY: 0.00176 AC XY: 131 AN XY: 74446

Gnomad4 AFR AF: 0.00318

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000882

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00108 Hom.: 1

Bravo AF: 0.00186

ExAC AF: 0.00116 AC: 141

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000927

EpiControl AF: 0.00214

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypercholesterolemia, familial, 4 Pathogenic:2 Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 18, 2001	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jul 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 rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	May 24, 2021	Identified at heterozygous status in a patient with clinical suspect of Familial Hypercholesterolemia without pathogenic variants in LDLR, APOB, PCSK9, APOE, STAP1, ABCG5, ABCG8, LIPA and other lipid-related genes by next-generation sequencing. Likely pathogenic if in trans with an additional LDLRAP1 variant; probably affecting cholesterol levels at heterozygous status. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jun 02, 2017

Variant summary: The c.605C>A (p.Ser202Tyr) in LDLRAP1gene is a missense change that involves a non-conserved nucleotide. The variant is located outside of any known domain or repeat. 4/4 in silico tools predict damaging outcome (SNP&GO not captured due to low reliability index), however no functional studies supporting these predictions were published at the time of evaluation. The variant is present in the large control population dataset of ExAC at a frequency of 0.001165 (140/ 120202 chrs tested), which exceeds the maximal expected frequency of a pathogenic allele (0.00079) in this gene. However, in ExAC, this variant is identified in cis with c.604T>C leading to the c.604_605delinsCA (p.Ser202His) in 73 individuals (~50%), altering its functional interpretation. The c.605C>A was identified heterozygously in affected individual without strong evidence for causality. One reputable database/clinical laboratory cite the variant with an outdated classification. Taking all lines of evidence into consideration, the variant was classified as VUS-Possibly Benign until more information becomes available. -

Familial hypercholesterolemia Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Jan 11, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.072	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	2.4e-8	A
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.098
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.019	D
Polyphen		0.97	D
Vest4		0.36
MVP		0.71
MPC		0.42
ClinPred		0.019	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.079
gMVP		0.32

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: rs121908326; hg19: chr1-25889633;