NM_000527.5:c.1617C>T
Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1
The NM_000527.5(LDLR):c.1617C>T(p.Pro539Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0551 in 1,612,458 control chromosomes in the GnomAD database, including 4,226 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Consequence
NM_000527.5 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -21 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.1617C>T | p.Pro539Pro | synonymous_variant | Exon 11 of 18 | ENST00000558518.6 | NP_000518.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0726 AC: 11031AN: 152010Hom.: 614 Cov.: 32
GnomAD3 exomes AF: 0.0756 AC: 19015AN: 251466Hom.: 1180 AF XY: 0.0735 AC XY: 9993AN XY: 135908
GnomAD4 exome AF: 0.0532 AC: 77739AN: 1460330Hom.: 3609 Cov.: 30 AF XY: 0.0536 AC XY: 38940AN XY: 726536
GnomAD4 genome AF: 0.0726 AC: 11048AN: 152128Hom.: 617 Cov.: 32 AF XY: 0.0746 AC XY: 5546AN XY: 74372
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Benign:8
Due to the increased occurrence of the mutation (>= 5%), this variant is classified as benign. -
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This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
8/95 non-FH individuals; MAF = 4,7% in 86 Spanish healthy individuals -
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not specified Benign:3
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Familial hypercholesterolemia Benign:3
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not provided Benign:2
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Variant summary: This LDLR c.1617C>T variant affects a non-conserved nucleotide, resulting in synonymous amino acid change. 5/5 splice-site tools via Alamut predict that this variant does not affect normal splicing. This variant was found in 9229/121288 control chromosomes from the large and broad populations of ExAC at a frequency of 0.0760916 including several homozygotes, which is over 60 times greater than the maximal expected frequency of a pathogenic LDLR allele (0.0012508), suggesting this variant is benign. The variant has also been reported to co-occur with other potentially pathogenic variants such as c.68-1G>A (internal finding in one specimen), c.1634G>A (internal finding in one specimen), and p. p.Cys667Ser (Zakharova_2005), further supporting the benign outcome. Additionally, the variant is reported in the literature to be a common polymorphism that has no effect on plasma triglyceride, HDL cholesterol, apoA1 or lipoprotein (a) levels (Wu_Atheroscl_1999). Taken together, this variant has been classified as Benign. -
Smith-Lemli-Opitz syndrome Benign:1
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Cardiovascular phenotype Benign:1
This alteration is classified as 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