Submissions for variant NM_000527.5(LDLR):c.1186+5G>A

dbSNP: rs879254821

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000237711	SCV001960922	likely pathogenic	Hypercholesterolemia, familial, 1	2021-06-08	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.1186+5G>A variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PS3_Moderate, PS4_Moderate and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - No population data was found for this variant in gnomAD (gnomAD v2.1.1). PS3_moderate - Level 2 FS: PMID:21990180 - study on htz patient's lymhocytes. FACS + CSLM + Nothern blot were used. 50% biosynthetic process; 65% binding; 60% clearance. Abnormal transcript: retention of part of intron 8 causing a frameshift and premature stop codon (LDLR:p.G396fs*26) then identified by cDNA sequencing. PS4_moderate - Variant meets PM2 and was found in 8 unrelated FH cases. PP4 - Variant meets PM2. Variant found in 8 FH cases fulfilling validated clinical criteria.
LDLR-LOVD, British Heart Foundation	RCV000237711	SCV000295266	pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000237711	SCV000583800	likely pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Fundacion Hipercolesterolemia Familiar	RCV000237711	SCV000607568	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Iberoamerican FH Network	RCV000237711	SCV000748141	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV001039692	SCV001203233	likely pathogenic	Familial hypercholesterolemia	2023-05-04	criteria provided, single submitter	clinical testing	This sequence change falls in intron 8 of the LDLR gene. It does not directly change the encoded amino acid sequence of the LDLR protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with familial hypercholesterolemia (PMID: 12436241, 18096825, 23833242, 26342331, 33740630; Invitae). This variant is also known as IVS8+5G>A. ClinVar contains an entry for this variant (Variation ID: 251706). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001039692	SCV001448367	pathogenic	Familial hypercholesterolemia	2020-11-02	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.1186+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: three predict the variant abolishes a 5' splicing donor site, one predict the variant weakens a 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Etxebarria_2012). The variant was absent in 249224 control chromosomes (gnomAD). c.1186+5G>A has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (e.g. Etxebarria_2012, Amsellem_2002, Minicocci_2015, Kusters_2013). These data indicate that the variant is very likely to be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant causes decreased expression, LDL binding, and LDL internalization (Etxebarria_2012). Five submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 (without evidence for independent evaluation), and classified the variant as pathogenic (1x) / likely pathogenic (2x), or VUS (2x). Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000237711	SCV000606343	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research