Submissions for variant NM_000527.5(LDLR):c.214del (p.Asp72fs)

dbSNP: rs879254438

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000238154	SCV000294534	pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Fundacion Hipercolesterolemia Familiar	RCV000238154	SCV000607431	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
GeneDx	RCV000599126	SCV000709931	pathogenic	not provided	2018-02-14	criteria provided, single submitter	clinical testing	The c.214delG pathogenic variant in the LDLR gene (also reported as 211delG due to alternate nomenclature) has been reported in several individuals with FH from various ethnic backgrounds, and was found to segregate with FH in one large family from Northern Ireland (Ward et al., 1996; Mozas et al., 2000; Humphries et al., 2006). Furthermore, the c.214delG variant has not been observed at a significant frequency in large population cohorts (Lek et al., 2016). This variant causes a shift in reading frame starting at codon aspartic acid (Asp), changing it to a threonine (Thr), and creating a premature stop codon at position 134 of the new reading frame, denoted p.Asp72ThrfsX134. This pathogenic variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Moreover, other frameshift variants in the LDLR gene have been reported in Human Gene Mutation Database in association with FH (Stenson et al., 2014), indicating that loss of function is a mechanism of disease for this gene.
Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen	RCV000238154	SCV000987021	pathogenic	Hypercholesterolemia, familial, 1	2018-03-01	criteria provided, single submitter	clinical testing	The mutation leads to the amino acid exchange asparagine to threonine at position 72 at protein level, as well as a premature termination of protein synthesis. This variant was previously observed in patients with FH under the legacy name c.211delG. We observed this variant in a patient with TC up to 320 mg/dl and LDL-C approx 290 mg/dl at the age of 35. PMID: 8645375 10790219
Labcorp Genetics (formerly Invitae), Labcorp	RCV001854885	SCV002173663	pathogenic	Familial hypercholesterolemia	2023-09-26	criteria provided, single submitter	clinical testing	This variant is present in population databases (rs761105623, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Asp72Thrfs*134) in the LDLR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073). This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 8645375). It has also been observed to segregate with disease in related individuals. This variant is also known as 211delG. ClinVar contains an entry for this variant (Variation ID: 251078). For these reasons, this variant has been classified as Pathogenic.
AiLife Diagnostics, AiLife Diagnostics	RCV000599126	SCV002502749	pathogenic	not provided	2021-09-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002429163	SCV002731215	pathogenic	Cardiovascular phenotype	2017-08-29	criteria provided, single submitter	clinical testing	The c.214delG pathogenic mutation, located in coding exon 3 of the LDLR gene, results from a deletion of one nucleotide at nucleotide position 214, causing a translational frameshift with a predicted alternate stop codon (p.D72Tfs*134). This mutation (also reported as c.211delG) has been detected in multiple individuals with familial hypercholesterolemia (FH), including one large family with segregation reported across several generations (Ward AJ et al. Atherosclerosis, 1996 Feb;120:83-91; Mozas P et al. Hum. Mutat., 2000 May;15:483-4; Junyent M et al. Arterioscler. Thromb. Vasc. Biol., 2008 Mar;28:580-6). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017537	SCV004847775	pathogenic	Homozygous familial hypercholesterolemia	2019-10-11	criteria provided, single submitter	clinical testing	The p.Asp72ThrfsX134 variant in LDLR has been identified in at least 3 individuals with hypercholesterolemia and segregated with disease in >15 individuals from a large family (Ward 1996, Martin 2016, Defesche 2017). It has also been identified in 1/113766 European chromosomes by gnomAD (https://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 72 and leads to a premature termination codon 134 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the LDLR gene is an established disease mechanism in autosomal dominant familial hypercholesterolemia. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant familial hypercholesterolemia. ACMG/AMP Criteria applied: PVS1, PP1_Strong, PM2, PS4_Supporting.