ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.1035GAA[1] (p.Lys346del) (rs727502987)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000150537 SCV000197753 uncertain significance not specified 2014-06-19 criteria provided, single submitter clinical testing The Lys346del variant in DSG2 has been reported in 2 individuals with ARVC and w as absent from 1400 control chromosomes (Tan 2010, Quarta 2011). In addition, th is variant has been identified by our laboratory in 1 individual with HCM (LMM u npublished data). Two of these individuals (Tan 2010, LMM) carried other likely pathogenic variants, including 1 in the DSG2 gene on the other allele (in trans) . This variant is a deletion of 1 amino acid at position 346 and is not predicte d to alter the protein reading-frame, though it is unclear if this deletion will impact the protein. In summary, the clinical significance of the Lys346del vari ant is uncertain.
GeneDx RCV000766862 SCV000233521 uncertain significance not provided 2019-01-09 criteria provided, single submitter clinical testing The c.1038_1040delGAA variant in the DSG2 gene has been reported previously in association with ARVC (Tan et al., 2010; Quarta et al., 2014). Tan et al. (2010) initially reported the c.1038_1040delGAA variant in one individual diagnosed with ARVC who also harbored a splice site variant in the DSG2 gene. Quarta et al. (2014) identified the c.1038_1040delGAA variant in one individual diagnosed with ARVC from a cohort of patients evaluated in the UK and found the variant to be absent in 300 controls. Functional studies were not performed and segregation data was not provided in either study. The c.1038_1040delGAA variant results in an in-frame deletion of a single Lysine residue at position 346 of the DSG2 gene, denoted p.Lys346del. The deleted Lysine residue occurs at a position that is conserved among mammals. Lastly, the c.1038_1040delGAA variant was not observed in approximately 5,900 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000820567 SCV000961284 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2020-05-26 criteria provided, single submitter clinical testing This variant, c.1038_1040delGAA, results in the deletion of 1 amino acid(s) of the DSG2 protein (p.Lys346del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 21606390, 20857253, 27532257). ClinVar contains an entry for this variant (Variation ID: 163205). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the affected amino acid(s) is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000852474 SCV000995168 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2017-02-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV001185997 SCV001352322 uncertain significance Cardiomyopathy 2019-11-27 criteria provided, single submitter clinical testing

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