NM_000527.5:c.67+1G>A
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_000527.5(LDLR):c.67+1G>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000186 in 1,611,068 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000527.5 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.67+1G>A | splice_donor_variant, intron_variant | Intron 1 of 17 | ENST00000558518.6 | NP_000518.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152182Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000412 AC: 1AN: 242948Hom.: 0 AF XY: 0.00000755 AC XY: 1AN XY: 132538
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1458886Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2AN XY: 725610
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152182Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74352
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:2
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Homozygous familial hypercholesterolemia Pathogenic:1
The c.67+1G>A variant in LDLR has been reported in 1 individual with hypercholesterolemia (Nauck 1998; http://www.ucl.ac.uk/fh-old/muttab.html). This variant has also been identified in 1/107726 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/) and is reported in ClinVar (Variation ID: 431507). This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Heterozygous loss of function of the LDLR gene is an established disease mechanism in individuals with familial hypercholesterolemia (FH). In summary, this variant meets criteria to be classified as pathogenic for FH in an autosomal dominant manner based upon predicted impact to the protein. ACMG/AMP Criteria applied: PVS1, PM2. -
Familial hypercholesterolemia Pathogenic:1
This sequence change affects a donor splice site in intron 1 of the LDLR gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of this splice site has been observed in individual(s) with familial hypercholesterolemia (PMID: 32770674). ClinVar contains an entry for this variant (Variation ID: 431507). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at