rs386629678

Positions:

• chr1-25563141-TC-CA
• chr1-25563141-TC-CG

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PS1_Moderate PM2 PM5 BP6

The ENST00000374338.5(LDLRAP1):​c.604_605delinsCA​(p.Ser202His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S202Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: LDLRAP1 ENST00000374338.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• 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 Uncertain_significance. Variant got 5 ACMG points.

• PS1: Transcript ENST00000374338.5 (LDLRAP1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM2: Very rare variant in population databases, with high coverage
• 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.
• BP6: Variant 1-25563141-TC-CA is Benign according to our data. Variant chr1-25563141-TC-CA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 241063.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=4}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLRAP1	NM_015627.3	c.604_605delinsCA	p.Ser202His	missense_variant	6/9	ENST00000374338.5	NP_056442.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLRAP1	ENST00000374338.5	c.604_605delinsCA	p.Ser202His	missense_variant	6/9	1	NM_015627.3	ENSP00000363458	P1
LDLRAP1	ENST00000484476.5	n.326_327delinsCA		non_coding_transcript_exon_variant	1/4	1
LDLRAP1	ENST00000488127.1	n.1074_1075delinsCA		non_coding_transcript_exon_variant	5/7	2

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypercholesterolemia, familial, 4 Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Mar 30, 2023	This multi-nucleotide sequence change in LDLRAP1 is predicted to replace serine with histidine at codon 202, p.(Ser202His). The serine residue is weakly conserved (100 vertebrates, UCSC), and is a predicted phosphoserine residue. There is a moderate physicochemical difference between serine and histidine. This multi-nucleotide variant (MNV) is present in 332 alleles (including 2 homozygotes) out of approximately 281,788 alleles in gnomAD v2.1 (global population frequency ~0.1%). The MNV has been reported to segregate with hypercholesterolaemia as a consanguineous homozygous occurrence in two affected siblings (PMID: 11326085). It has been reported with conflicting interpretations, as a variant of uncertain significance and likely benign (ClinVar ID: 241063). Multiple lines of computational evidence predict a benign effect for the missense substitution (5/5 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PP1, BP4. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Feb 12, 2024

Variant summary: LDLRAP1 c.604_605delinsCA (p.Ser202His) results in a non-conservative amino acid change in the encoded protein sequence. Three of three in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0012 in 281882 control chromosomes in the gnomAD database, including 2 homozygotes. This frequency is not significantly higher than expected for a pathogenic variant in LDLRAP1 causing Early Onset Coronary Artery Disease (0.0012 vs 0.0063), however the presence of the homozygous individuals is supporting evidence that the variant is benign. c.604_605delinsCA has been reported in the literature in individuals affected with Familial Hypercholesterolemia and Acute Coronary Syndrome (Erasmo_2021, Ghaleb_2022, Salamanca_2017 and Sanchez_2019). In one study of a large Familial Hypercholesterolemia family, the variant was found along with two other variants in relevant genes (LPR6, CYP7A1) in two family members with severe disease, while two less-severely affected family members carried the other two variants but not LDLRAP1 p.Ser202His (Ghaleb_2022). In addition, three unaffected family members carried the variant of interest alone or with one additional variant. This suggests a lack of segregation of the variant with disease in this family. These reports do not provide unequivocal conclusions about association of the variant with Early Onset Coronary Artery Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34496902, 28958330, 35323704, 31153816). ClinVar contains an entry for this variant (Variation ID: 241063). Based on the evidence outlined above, the variant was classified as likely benign. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 08, 2022

See Variant Classification Assertion Criteria. -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 04, 2018

This alteration is classified as likely 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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs386629678; hg19: chr1-25889632;