Submissions for variant NM_018255.4(ELP2):c.293dup (p.Leu98fs)

dbSNP: rs529659464

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV001335775	SCV001529008	pathogenic	Intellectual disability, autosomal recessive 58	2018-05-10	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx	RCV003223717	SCV003919433	uncertain significance	not provided	2023-04-21	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV001335775	SCV004013354	likely pathogenic	Intellectual disability, autosomal recessive 58	2023-06-29	criteria provided, single submitter	clinical testing	PVS1, PM3
Illumina Laboratory Services, Illumina	RCV001335775	SCV004101339	likely pathogenic	Intellectual disability, autosomal recessive 58	2023-08-24	criteria provided, single submitter	clinical testing	The ELP2 c.293dup (p.Leu98PhefsTer10) variant causes a shift in the protein reading frame that is predicted to result in premature termination of the protein. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. This variant has been reported in trans with a missense variant in two individuals with an intellectual developmental disorder (PMID: 33976153). The highest frequency of the p.Leu98PhefsTer10 variant in the Genome Aggregation Database is 0.001183 in the African/African American population (version 3.1.2). Based on the available evidence, the c.293dup (p.Leu98PhefsTer10) variant is classified as likely pathogenic for intellectual developmental disorder.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV003223717	SCV004847460	uncertain significance	not provided	2024-03-19	criteria provided, single submitter	clinical testing	The p.Leu98PhefsX10 variant in ELP2 has been reported in 1 individual with syndromic intellectual disability and segregated with disease in 1 affected individuals from 1 family (Kojic 2021 PMID: 33976153). This variant has been identified in 0.12% (49/41418) of African/African American chromosomes by gnomAD (http://gnomad.broadinstitute.org, v3.1.2). This variant has also been reported in ClinVar (Variation ID 1012186). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 98 and leads to a premature termination codon 10 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Other loss of function variants have been reported in at least 6 individuals with autosomal recessive intellectual developmental disorder (Kojic 2021 PMID: 33976153, Russo PMID: 34653680, Lunke 2020 PMID: 32573669); however the role of loss of function in the disease mechanism is still uncertain. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PVS1_Moderate, PP1.
Wainwright Lab, University Of Queensland	RCV001310088	SCV001482310	likely pathogenic	Intellectual disability, profound		no assertion criteria provided	clinical testing