Submissions for variant NM_032607.3(CREB3L3):c.732dup (p.Lys245fs)

gnomAD frequency: 0.00038  dbSNP: rs780374391

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics, University of Leipzig Medical Center	RCV001780210	SCV002026425	uncertain significance	Hypertriglyceridemia 2	2021-10-20	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PVS1_STR, PS4_SUP
Labcorp Genetics (formerly Invitae), Labcorp	RCV002069370	SCV002370987	likely benign	not provided	2024-01-17	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV002069370	SCV002501413	uncertain significance	not provided	2021-05-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004690038	SCV005184713	uncertain significance	not specified	2024-05-13	criteria provided, single submitter	clinical testing	Variant summary: CREB3L3 c.732dupG (p.Lys245GlufsX130) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00046 in 250596 control chromosomes, suggesting the variant could be benign. However, c.732dupG or nearby variant(s) resulting in the same protein effect have been reported in the literature in multiple individuals affected with Hypertriglyceridemia 2, including as a heterozygous genotype in multiple familial pedrigrees showing autosomal dominant transmission, or was reported in unaffected individuals (e.g. Lee_2011, Johnston_2015, Deshotels_2022, Ying_2023). Polygenic risk scores calculated in several of these studies have led to reporting of this variant as a risk factor for the development of Hypertriglyceridemia, citing additional evidence that individuals with severe hypertriglyceridemia were found to be 20X more likely to carry a heterozygous LOF variant in CREB3L3 (e.g. Dron_2020). These data indicate that the variant is possibly to be associated with disease. 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: 36325899, 26046366, 21666694, 37940981, 32580631). ClinVar contains an entry for this variant (Variation ID: 979022). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
GBinsight Genetic Testing by GB HealthWatch, Genben Lifesciences Corporation	RCV001257913	SCV001328433	pathogenic	Hypertriglyceridemia 1	2020-05-27	no assertion criteria provided	clinical testing	Multiple, unrelated, probands were referred, from independent clinics, for clinical genetic testing for familial hyperchtriglyceridemia. Probands were referred for clinical genetic testing presented with severe hypertriglyceridemia, low HDL-cholesterol and type 2 diabetes. Clinical genetic testing identified heterozygosity for the p.Lys245GlufsTer130 (NM_032607.3:c.732dupG) genetic variant in the the germline. The pathogenicity of this variant is supported by several publications that have demonstrated that this variant is a loss-of-function and is a cause of severe hypertriglyceridemia.