rs141522360
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_015627.3(LDLRAP1):āc.626C>Gā(p.Thr209Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000682 in 1,613,708 control chromosomes in the GnomAD database, including 1 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 Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T209I) has been classified as Uncertain significance.
Frequency
Consequence
NM_015627.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLRAP1 | NM_015627.3 | c.626C>G | p.Thr209Ser | missense_variant | 7/9 | ENST00000374338.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLRAP1 | ENST00000374338.5 | c.626C>G | p.Thr209Ser | missense_variant | 7/9 | 1 | NM_015627.3 | P1 | |
LDLRAP1 | ENST00000484476.5 | n.348C>G | non_coding_transcript_exon_variant | 2/4 | 1 | ||||
LDLRAP1 | ENST00000474283.1 | n.37C>G | non_coding_transcript_exon_variant | 1/3 | 3 | ||||
LDLRAP1 | ENST00000488127.1 | n.1096C>G | non_coding_transcript_exon_variant | 6/7 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152212Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 250554Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135562
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461378Hom.: 1 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 726990
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152330Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74494
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 4 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 25, 2021 | This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 209 of the LDLRAP1 protein (p.Thr209Ser). This variant is present in population databases (rs141522360, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with LDLRAP1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 24, 2023 | Variant summary: LDLRAP1 c.626C>G (p.Thr209Ser) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 250554 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, c.626C>G has been not been reported in the literature in individuals affected with Familial Hypercholesterolemia and no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 32041611). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 19, 2023 | The c.626C>G (p.T209S) alteration is located in exon 7 (coding exon 7) of the LDLRAP1 gene. This alteration results from a C to G substitution at nucleotide position 626, causing the threonine (T) at amino acid position 209 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at