Submissions for variant NM_015141.4(GPD1L):c.247G>A (p.Glu83Lys)

gnomAD frequency: 0.00018  dbSNP: rs72552292

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000477992	SCV000566045	uncertain significance	not provided	2022-08-25	criteria provided, single submitter	clinical testing	Reported in one male with sudden infant death syndrome (SIDS) and one individual with Brugada syndrome (van Norstrand et al., 2007; van Lint et al., 2019); Functional studies demonstrate that the E83K variant exhibits significantly less enzymatic activity than wild type GPD1L, resulting in reduction in sodium channel current (Van Norstrand et al., 2007; Valdivia et al., 2009); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19606473, 21937582, 30662450, 25395996, 31043699, 30847666, 31980526, 19666841, 34957250, 29077258, 17967976)
Ambry Genetics	RCV000618850	SCV000736159	likely benign	Cardiovascular phenotype	2023-12-19	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000793005	SCV000932338	uncertain significance	Brugada syndrome	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 83 of the GPD1L protein (p.Glu83Lys). This variant is present in population databases (rs72552292, gnomAD 0.03%). This missense change has been observed in individual(s) with cardiac disease (PMID: 17967976, 30847666, 31980526). ClinVar contains an entry for this variant (Variation ID: 787). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GPD1L protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GPD1L function (PMID: 17967976, 19666841). 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.
AiLife Diagnostics, AiLife Diagnostics	RCV000477992	SCV002503362	uncertain significance	not provided	2020-06-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000000823	SCV002814492	uncertain significance	Brugada syndrome 2	2021-10-29	criteria provided, single submitter	clinical testing
OMIM	RCV000000823	SCV000020973	pathogenic	Brugada syndrome 2	2007-11-13	no assertion criteria provided	literature only
GeneReviews	RCV000000823	SCV000188926	not provided	Brugada syndrome 2		no assertion provided	literature only
Clinical Genetics, Academic Medical Center	RCV000477992	SCV001924641	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000477992	SCV001927264	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000477992	SCV001954139	uncertain significance	not provided		no assertion criteria provided	clinical testing