ClinVar Miner

Submissions for variant NM_001130009.3(GEN1):c.2652A>C (p.Glu884Asp)

gnomAD frequency: 0.00629  dbSNP: rs141534568
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001355346 SCV001725053 benign not provided 2025-01-26 criteria provided, single submitter clinical testing
Breakthrough Genomics, Breakthrough Genomics RCV001355346 SCV005245756 benign not provided criteria provided, single submitter not provided
Ambry Genetics RCV004927698 SCV005591610 likely benign not specified 2024-10-02 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001355346 SCV001550212 likely benign not provided no assertion criteria provided clinical testing The GEN1 p.E884D variant was not identified in the literature nor was it identified in ClinVar. The variant was identified in dbSNP (ID: rs141534568) and in control databases in 637 of 269910 chromosomes (5 homozygous) at a frequency of 0.002360, and was observed at the highest frequency in the African population in 509 of 24520 chromosomes (freq: 0.02076) (5 homozygous) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.E884 residue is not conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) do not suggest a high likelihood of impact to the protein. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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