Submissions for variant NM_000527.5(LDLR):c.1199_1207del (p.Tyr400_Phe402del)

dbSNP: rs879254826

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000237319	SCV004022380	likely pathogenic	Hypercholesterolemia, familial, 1	2023-03-20	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.1199_1207del (p.Tyr400_Phe402del) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PS4, PM2, PM4, and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PS4: Variant meets PM2 and is identified in 19 unrelated FH index cases (18 with DLCN criteria>=6 from PMID: 18243212 (Alonso et al., 2008), and 1 with DLCN criteria from PMID 27784735 (Sánchez-Hernández et al.,2016)). So PS4 is met. PM2: This variant is absent from gnomAD (gnomAD v2.1.1). So PM2 is met. PM4: Variant meets PM2 and is in frame deletion. So PM4 is met. PP4: Variant meets PM2 and is identified in 19 unrelated index cases who fulfill clinical criteria for FH (see PS4 for details). So PP4 is met.
LDLR-LOVD, British Heart Foundation	RCV000237319	SCV000295291	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Fundacion Hipercolesterolemia Familiar	RCV000237319	SCV000607572	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781507	SCV000919589	pathogenic	Familial hypercholesterolemia	2018-12-11	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.1199_1207delACCTCTTCT (p.Tyr400_Phe402del), also known as c.1197_1205del9, results in an in-frame deletion that is predicted to remove 3 amino acids from the encoded protein. The variant was absent in 276812 control chromosomes (gnomAD). The variant, c.1199_1207delACCTCTTCT, has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia, including one homozygote, and is one of the most common variants in the Spanish populations (Alonso_2008, Sanchez-Hernandez_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000781507	SCV002176461	pathogenic	Familial hypercholesterolemia	2023-08-04	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Leu401 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9104431, 21722902, 24507775, 25461735). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 251727). This variant is also known as c.1197_2205del9. This variant has been observed in individuals with familial hypercholesterolemia (PMID: 18243212). This variant is not present in population databases (gnomAD no frequency). This variant, c.1199_1207del, results in the deletion of 3 amino acid(s) of the LDLR protein (p.Tyr400_Phe402del), but otherwise preserves the integrity of the reading frame.
Ambry Genetics	RCV002347939	SCV002644763	pathogenic	Cardiovascular phenotype	2021-06-18	criteria provided, single submitter	clinical testing	The c.1199_1207delACCTCTTCT pathogenic mutation (also known as p.Y400_F402del) is located in coding exon 9 of the LDLR gene. This pathogenic mutation results from an in-frame ACCTCTTCT deletion at nucleotide positions 1199 to 1207. This results in the in-frame deletion of 3 amino acids at codon 400. This mutation has been detected in numerous individuals with familial hypercholesterolemia, including heterozygous (HeFH) and homozygous (HoFH) cases, and it has been suggested as a founder mutation in the Grand Canary Islands of Spain; furthermore, significant co-segregation with disease has been reported in multiple families (Mozas P et al. Hum Mutat, 2004 Aug;24:187; Alonso R et al. Atherosclerosis, 2008 Oct;200:315-21; Alonso R et al. J Clin Lipidol 2016 Apr;10:953-961; Sánchez-Hernández RM et al. J Clin Lipidol 2019 May;13:618-626). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000237319	SCV000606354	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research