rs386629678

Variant names:

• chr1-25563141-TC-CA
• rs386629678
• NM_015627.3:c.604_605delTCinsCA

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_015627.3(LDLRAP1):​c.604_605delTCinsCA​(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. The variant is present in control chromosomes in GnomAd MNV project. The variant allele was found at a frequency of 0.00118 in 332 alleles, including 2 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. 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. S202Y) has been classified as Uncertain significance.

• Frequency: GnomAD MNV: 𝑓 0.0012 Genomes: not found (cov: 31)
• Consequence: LDLRAP1 NM_015627.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 0.592
• Publications: 4 publications found

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]

LDLRAP1 Gene-Disease associations (from GenCC):

• hypercholesterolemia, familial, 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• 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 VariationId is 241063.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLRAP1	NM_015627.3	c.604_605delTCinsCA	p.Ser202His	missense_variant		ENST00000374338.5	NP_056442.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLRAP1	ENST00000374338.5	c.604_605delTCinsCA	p.Ser202His	missense_variant		1	NM_015627.3	ENSP00000363458.4

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

GnomAD MNV AF: 0.00118 AC: 332 Hom.: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypercholesterolemia, familial, 4 Uncertain:2 Benign:1

Mar 30, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

Apr 29, 2025

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: LDLRAP1 c.604_605delinsCA (p.Ser202His) results in a non-conservative amino acid change in the encoded protein sequence. Two of two 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, predominantly at a frequency of 0.003 within the African or African-American subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in LDLRAP1 causing Early Onset Coronary Artery Disease (0.0012 vs 0.0063), allowing no conclusion about variant significance. 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. -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Dec 08, 2022

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

Cardiovascular phenotype Benign:1

May 04, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.59

Splicing

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

Other links and lift over

dbSNP: rs386629678; hg19: chr1-25889632;