chr1-25563141-TC-CA
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
Consequence
NM_015627.3 missense
Scores
Clinical Significance
Conservation
Publications
- hypercholesterolemia, familial, 4Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
- homozygous familial hypercholesterolemiaInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Likely_benign. The variant received -1 ACMG points.
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
GnomAD4 genome
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 4 Uncertain:2Benign:1
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. -
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not specified Benign:2
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. -
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not provided Benign:1
See Variant Classification Assertion Criteria. -
Cardiovascular phenotype Benign:1
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at