rs121908326
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM5BP4_ModerateBS2
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
Consequence
NM_015627.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
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: 249AN: 152136Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00115 AC: 289AN: 250500Hom.: 2 AF XY: 0.00116 AC XY: 157AN XY: 135524
GnomAD4 exome AF: 0.000755 AC: 1103AN: 1461688Hom.: 6 Cov.: 34 AF XY: 0.000822 AC XY: 598AN XY: 727188
GnomAD4 genome ? AF: 0.00165 AC: 251AN: 152254Hom.: 0 Cov.: 32 AF XY: 0.00176 AC XY: 131AN XY: 74446
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 4 Pathogenic:2Uncertain:1Benign:2
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. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | May 18, 2001 | - - |
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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | - | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 16, 2024 | Variant summary: LDLRAP1 c.605C>A (p.Ser202Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00084 in 1613942 control chromosomes in the gnomAD database, including 6 homozygotes. c.605C>A has been reported in the literature in multiple heterozygous individuals affected with or with clinical features of Familial Hypercholesterolemia, without strong evidence for causality, with frequent reporting as a VUS (e.g. Rubba_2017, Luirink_2019, Rieck_2020, Rimbert_2022). These reports do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. 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: 25911074, 11326085, 30795984, 32770674, 35047021, 28353356). ClinVar contains an entry for this variant (Variation ID: 4776). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. - |
Familial hypercholesterolemia Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 11, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at