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

gnomAD frequency: 0.00011  dbSNP: rs72552291

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000170923	SCV000223481	uncertain significance	not provided	2023-03-01	criteria provided, single submitter	clinical testing	Functional studies suggest that p.(A280V) interferes with the trafficking of cardiac SCN5A sodium channels to the plasma membrane and reduces inward sodium current (London 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: 22995991, 19745168, 23414114, 17967977, 27435932, 30662450, 30821013, 34426522, 31019026, 31980526, 28798025, 19666841, 31618753)
Ambry Genetics	RCV000244771	SCV000320306	uncertain significance	Cardiovascular phenotype	2022-08-05	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, but 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 performed in vitro 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 when co-expressed with SCN5A; however, it's unclear that this variant will have the same functional impact in vivo (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). Based on data from gnomAD, the T allele has an overall frequency of 0.01% (36/279634) total alleles studied. The highest observed frequency of 0.02% (25/126354) alleles in the non-Finnish European population is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). 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. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Laboratory for Molecular Medicine, Mass General Brigham 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 (http://gnomad.broadinstitute.org). 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	2023-12-06	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 280 of the GPD1L protein (p.Ala280Val). This variant is present in population databases (rs72552291, gnomAD 0.02%). This missense change has been observed in individual(s) with Brugada syndrome (PMID: 17967977, 26743238, 27435932). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 786). 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: 17967977, 19666841, 19745168, 20724705). 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.
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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000000822	SCV002768342	uncertain significance	Brugada syndrome 2	2020-06-11	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as VUS - 3B. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. Functional analysis of a missense has proven a loss of function consequence, however the pathogenicity of this variant is uncertain (PMID: 17967977, PMID: 19666841). (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0112 - Variants in this gene are known to have reduced penetrance (PMID: 17967977), however only a single example has been observed. (N) 0200 - Variant is predicted to result in a missense amino acid change from an alanine to a valine (exon 6). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD v2 <0.001 for a dominant condition (36 heterozygotes, 0 homozygotes). (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD v2 (12 heterozygotes, 0 homozygotes). (N) 0503 - Missense variant consistently predicted to be tolerated or not conserved in mammals with a minor amino acid change. (B) 0600 - Variant is located in an annotated domain or motif, (NAD_Gly3P_dh_C terminal domain; PDB). (N) 0705 - No comparable variants have previous evidence for pathogenicity. An alternative change (p.Ala280Thr) has been reported as a VUS in a patient who died suddenly (ClinVar). (N) 0808 - Previous reports of pathogenicity are conflicting. This variant has been reported in one large family, and several additional individuals who either died suddenly or had Brugada syndrome. However it has also been reported as a VUS, and as likely benign in an individual with left ventricular hypertrabeculation (ClinVar, PMID: 17967977, PMID: 27435932, PMID: 28798025, PMID: 26743238). (N) 1002 - Moderate functional evidence supporting abnormal protein function. This variant has been functionally proven in transfected HEK293 and COS7 cells to cause a signficant reductions in sodium current and channel formation. It also impairs SCN5A protein localization, and its ability to integrate into the channel (PMID: 17967977, PMID: 19666841). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Revvity Omics, Revvity	RCV000000822	SCV003815112	uncertain significance	Brugada syndrome 2	2020-10-12	criteria provided, single submitter	clinical testing
Dept of Medical Biology, Uskudar University	RCV003318331	SCV004022058	uncertain significance	Long QT syndrome	2024-01-08	criteria provided, single submitter	research	Criteria: BP4
OMIM	RCV000000822	SCV000020972	pathogenic	Brugada syndrome 2	2007-11-13	flagged submission	literature only
GeneReviews	RCV000000822	SCV000188927	not provided	Brugada syndrome 2		no assertion provided	literature only
Forensic Genetics Laboratory, Harris County Institute of Forensic Sciences	RCV000234995	SCV000263117	pathogenic	Death in infancy	2015-03-27	flagged submission	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192631	SCV001360881	likely pathogenic	Brugada syndrome (shorter-than-normal QT interval)	2019-06-10	flagged submission	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.