Submissions for variant NM_015141.4(GPD1L):c.560A>G (p.Asn187Ser)

dbSNP: rs951273802

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000692557	SCV000820384	uncertain significance	Brugada syndrome	2022-08-09	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 187 of the GPD1L protein (p.Asn187Ser). This variant is present in population databases (no rsID available, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with GPD1L-related conditions. ClinVar contains an entry for this variant (Variation ID: 571418). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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	RCV001196720	SCV001367351	uncertain significance	Brugada syndrome 2	2020-03-19	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: PM2,PP4.
Ambry Genetics	RCV002343465	SCV002648363	uncertain significance	Cardiovascular phenotype	2023-12-22	criteria provided, single submitter	clinical testing	The p.N187S variant (also known as c.560A>G), located in coding exon 5 of the GPD1L gene, results from an A to G substitution at nucleotide position 560. The asparagine at codon 187 is replaced by serine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786318	SCV000925093	uncertain significance	not provided	2018-02-06	no assertion criteria provided	provider interpretation	p.Asn187Ser (c.560A>G) in exon 5 of the GPD1L gene (NM_015141.3) Chromosome location 3:32188168 A / G Based on the information reviewed below, we classify this as a Variant of Uncertain Significance (VUS). ? According to the Invitae report, this variant has not been reported in the literature in association with disease. This is a conservative amino acid change, resulting in the replacement of a polar Asparagine with a polar Serine. Asparagine at this location is highly conserved across ~100 vertebrate species for which we have data (although it is instead a positively-charged Lysine in one species). The adjacent residues are also highly conserved. There are no Likely Pathogenic or Pathogenic variants currently listed in ClinVar within 10 amino acids to either side. According to the Invitae report, in silico algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant was reported in 2 non-Finnish European individuals in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Ancestry-specific minor allele frequency (MAF) = 0.002%. Overall MAF = 0.0008%. Our patient’s ancestry is from Russia. There is good coverage at this site. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases.