ClinVar Miner

Submissions for variant NM_015141.4(GPD1L):c.839C>T (p.Ala280Val) (rs72552291)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000170923 SCV000223481 pathogenic not provided 2017-06-30 criteria provided, single submitter clinical testing The Ala280Val variant in the GPD1L gene has been reported in one large, multigeneration family with multiple individuals with Brugada syndrome (London B et al., 2007). The Ala280Val variant co-segregated with a Brugada syndrome phenotype in 16 relatives, but was also identified in 27 asymptomatic relatives in the two youngest generations of the pedigree (London B et al., 2007). Functional studies suggested that the Ala280Val variant in GDP1L interferes with the trafficking of cardiac SCN5A sodium channels to the plasma membrane and reduces inward sodium current (London B et al., 2007; Valdivia C et al., 2009). While the 1000 Genomes database reports Ala280Val in 2/762 alleles (0.3%) from individuals of European ancestry (Kersey P et al., 2010), published controls studies did not identify Ala280Val in >1,000 control alleles (London B et al., 2007). Additionally, Ala280Val was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project indicating it is not a common benign variant in these populations.
Ambry Genetics RCV000244771 SCV000320306 likely pathogenic Cardiovascular phenotype 2017-08-17 criteria provided, single submitter clinical testing The p.A280V variant (also known as c.839C>T), located in coding exon 6 of the GPD1L gene, results from a C to T substitution at nucleotide position 839. The alanine at codon 280 is replaced by valine, an amino acid with similar properties. This variant has been reported to co-segregate with confirmed or suspected Brugada syndrome in multiple individuals in three generations in one family; however, the variant was also present in multiple unaffected individuals with uncertain phenotype, suggesting reduced penetrance (Weiss R et al. Circulation. 2002;105(6):707-13; London B et al. Circulation. 2007;116(20):2260-8). Functional studies have reported this variant to result in reduced SCN5A channel expression at the cell surface, by way of abnormal trafficking, and reduced inward sodium channel current (London B et al. Circulation. 2007;116(20):2260-8; Liu M et al. Circ Res. 2009;105(8):737-45; Valdivia CR et al. Am J Physiol. Heart Circ Physiol. 2009;297(4):H1446-52). In addition, based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability. This amino acid position is not well conserved in available vertebrate species, and valine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000614172 SCV000711800 uncertain significance not specified 2019-03-15 criteria provided, single submitter clinical testing The p.Ala280Val variant in GPD1L has been reported in 1 infant who died suddenly, 2 individuals with Brugada syndrome, and 1 individual with LVNC who also carried a likely pathogenic variant in TTN (Weiss 2002, London 2007, Alder 2016, Methner 2016. Miszalski-Jamka 2017). In vitro functional studies provide some evidence that the p.Ala280Val variant may impact protein function (London 2007, Liu 2009, Valdivia 2009); however, these types of assays may not accurately represent biological function. Furthermore, this variant has also been identified in 0.02% (25/126354) of European chromosomes by gnomAD ( Additionally, the alanine (Ala) at position 280 is not conserved, with 3 mammals (opossum, Tasmanian devil, wallaby) and >25 evolutionarily distant species carrying a valine (Val) at this position. These data raise the possibility that this change may be tolerated. Importantly, the validity of the GPD1L association with Brugada syndrome has been formally disputed by a ClinGen expert panel (Hosseini 2018). It had been implicated via a linkage-analysis based study (London 2007) resulting in the identification of the p.Ala280Val variant in a single family, in which it segregated with disease in many members (London 2007). However, this study did not convincingly exclude other genes in the linked region (including SCN5A), leaving it unclear whether the p.Ala280Val variant represented the causal variant. In summary, there is conflicting data for this variant and insufficient evidence supporting an association of the GPD1L gene with Brugada. Therefore, the clinical significance of the p.Ala280Val variant is uncertain. ACMG/AMP Criteria applied: PS3_Supporting, PS4_Supporting, BP4_Strong, BS1_Supporting.
Invitae RCV000638732 SCV000760276 uncertain significance Brugada syndrome 2019-12-06 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 280 of the GPD1L protein (p.Ala280Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs72552291, ExAC 0.01%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported to segregate with Brugada syndrome in a multigenerational family (PMID: 17967977). It has also been reported in an independent individual affected with Brugada syndrome and in an individual that suffered sudden death by unknown cause (PMID: 26743238, 27435932). ClinVar contains an entry for this variant (Variation ID: 786). Experimental studies have shown that this missense change reduces sodium channel current and trafficking, which affects surface membrane protein density and the number of functional channels (PMID: 17967977, 19666841, 19745168, 20724705). For these reasons, this allele has been classified as Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001192631 SCV001360881 likely pathogenic Brugada syndrome (shorter-than-normal QT interval) 2019-06-10 criteria provided, single submitter clinical testing Variant summary: GPD1L c.839C>T (p.Ala280Val) results in a non-conservative amino acid change located in the Glycerol-3-phosphate dehydrogenase, NAD-dependent, C-terminal domain (IPR006109) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 248254 control chromosomes (gnomAD). The observed variant frequency is approximately 27 fold of the estimated maximal expected allele frequency for a pathogenic variant in GPD1L causing Brugada Syndrome phenotype (5e-06), suggesting that the variant is benign or has low penetrance. c.839C>T has been reported in the literature in multiple individuals affected with Brugada Syndrome (London_2007, Adler_2016), including a large multi-generation family with several patients (London_2007). This variant has also been reported in a patient with left ventricular hypertrabeculation (Miszalski-Jamka_2017) and in an individual who suffered sudden death by an unknown cause (Methner_2016). These data indicate that the variant may be associated with disease. However, in one of these patients a co-occurrence with another pathogenic variant has also been reported (TTN, p.R10384X), providing supporting evidence for a benign role (Miszalski-Jamka_2017). Multiple publications report experimental evidence evaluating an impact on protein function and demonstrated that the A280V variant caused lower enzyme activity, and resulted in decreased surface expression of SCN5A with lower Na currents (London_2007, Valdivia_2009). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (2 pathogenic, 2 likely pathogenic, 1 VUS-favor pathogenic). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000000822 SCV001367729 uncertain significance Brugada syndrome 2 2018-11-21 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PP5,BP4.
OMIM RCV000000822 SCV000020972 pathogenic Brugada syndrome 2 2007-11-13 no assertion criteria provided literature only
GeneReviews RCV000000822 SCV000188927 pathogenic Brugada syndrome 2 2014-04-10 no assertion criteria provided literature only
Forensic Genetics Laboratory,Harris County Institute of Forensic Sciences RCV000234995 SCV000263117 pathogenic Death in infancy 2015-03-27 no assertion criteria provided clinical testing

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