rs879254830
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM4_SupportingPP5_Very_Strong
The NM_000527.5(LDLR):c.1207_1209delTTC(p.Phe403del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,964 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★★).
Frequency
Consequence
NM_000527.5 conservative_inframe_deletion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.1207_1209delTTC | p.Phe403del | conservative_inframe_deletion | Exon 9 of 18 | ENST00000558518.6 | NP_000518.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 29
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1460964Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 726802
GnomAD4 genome Cov.: 29
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:5Uncertain:1
PM2_Supporting+PM4+PS4_Moderate+PP4 -
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subject mutated among 2600 FH index cases screened = 1 -
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The NM_000527.5(LDLR):c.1207_1209del (p.Phe403del) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PM4, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 27 January 2023. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (v2.1.1). PM4: Variant meets PM2 and is an in-frame deletion. PS4_Supporting, PP4: Variant meets PM2 and was identified in at least 5 unrelated index cases who fulfill criteria for FH (4 patients from PMID 22698793 (Tichý et al., 2012) and 1 patient from PMID 11462246 (Nauck et al., 2001), reported as 1205delTCT). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at