19-11100303-G-T
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.148G>T (p.Ala50Ser) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying no ACMG/AMP evidence codes as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on October 28th, 2024. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023515/MONDO:0007750/013
Frequency
Consequence
NM_000527.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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LDLR | NM_000527.5 | c.148G>T | p.Ala50Ser | missense_variant | Exon 2 of 18 | ENST00000558518.6 | NP_000518.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000440 AC: 67AN: 152158Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000530 AC: 133AN: 251180Hom.: 0 AF XY: 0.000538 AC XY: 73AN XY: 135740
GnomAD4 exome AF: 0.000632 AC: 923AN: 1461492Hom.: 0 Cov.: 31 AF XY: 0.000597 AC XY: 434AN XY: 727038
GnomAD4 genome AF: 0.000440 AC: 67AN: 152276Hom.: 0 Cov.: 33 AF XY: 0.000443 AC XY: 33AN XY: 74450
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Uncertain:3Benign:10
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ACMG Guidelines: Pathogenic (ii) -
MAF =<0.3% -
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subjects mutated among 2600 FH index cases screened = 4 , 2 compound heterozygous / Software predictions: Benign -
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The NM_000527.5(LDLR):c.148G>T (p.Ala50Ser) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying no ACMG/AMP evidence codes as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on October 28th, 2024. -
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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
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not specified Uncertain:1Benign:3
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Variant summary: LDLR c.148G>T (p.Ala50Ser; also known as p.Ala29Ser) results in a conservative amino acid change located in the first class A repeat domain (IPR002172) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00054 in 262944 control chromosomes, predominantly at a frequency of 0.00097 within the Non-Finnish European subpopulation in the gnomAD database. However, in certain European regions the variant was found with a higher allele frequency, e.g. in the Swedish (0.0018), which is higher than estimated maximum expected for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (0.0013), suggesting that the variant might be benign. The variant, c.148G>T, has been reported in the literature in individuals affected with hypercholesterolemia, however it was also found in controls and individuals with low LDL cholesterol (Ahmad_2012, Beaudoin_2012, Brusgaard_2006, Chmarra_2010, Do_2015, Ebhardt_1999, Fouchier_2001, Jensen_1994, Junyent_2010, Koeijvoets_2005, Lange_2014, Leren_2004, Tejedor_2010, Geller_2018, Sustar_2022). These reports do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. In a family the variant was found to not segregate with disease (Jensen_1994). In addition, co-occurrences with other pathogenic variants have been reported (e.g. LDLR c.12G>A (p.Trp4X); Tejedor_2010 and LDLR c.1033C>T (p.Gln345X) in an internal LCA sample), providing supporting evidence for a benign role. 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: 23064986, 22923420, 16542394, 20145306, 25487149, 24055113, 10090484, 11810272, 30333156, 7820934, 19717150, 15823280, 24507775, 15199436, 10735632, 24956927, 28145427, 35913489, 20428891). ClinVar contains an entry for this variant (Variation ID: 68099). Based on the evidence outlined above, the variant was classified as likely benign. -
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 5 papers describe as VUS/nonpathogenic; ExAC: 0.1% (67/66532) European; ClinVar: 1 VUS -
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not provided Uncertain:1Benign:2Other:1
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This variant is associated with the following publications: (PMID: 27044878, 30333156, 7820934, 20506408, 18325082, 16542394, 15576851, 10090484, 26332594, 25487149, 25637381, 22390909, 24055113) -
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Familial hypercholesterolemia Benign:2
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Hypercholesterolemia Uncertain:1
Low GERP score may suggest that this variant may belong in a lower pathogenicity class -
LDLR-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Cardiovascular phenotype Benign:1
This alteration is classified as likely 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