rs72552291

chr3-32159096-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PP5_Strong BP4 BS2

The NM_015141.4(GPD1L):c.839C>T(p.Ala280Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000837 in 1,613,366 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A280T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000080 (1 hom.)
• Consequence: GPD1L NM_015141.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:3 U:8 O:1
• Conservation: PhyloP100: 1.36

Genes affected

GPD1L (HGNC:28956): (glycerol-3-phosphate dehydrogenase 1 like) The protein encoded by this gene catalyzes the conversion of sn-glycerol 3-phosphate to glycerone phosphate. The encoded protein is found in the cytoplasm, associated with the plasma membrane, where it binds the sodium channel, voltage-gated, type V, alpha subunit (SCN5A). Defects in this gene are a cause of Brugada syndrome type 2 (BRS2) as well as sudden infant death syndrome (SIDS). [provided by RefSeq, Jul 2010]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PP5: Variant 3-32159096-C-T is Pathogenic according to our data. Variant chr3-32159096-C-T is described in ClinVar as [Uncertain_significance]. Clinvar id is 786.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=8, Likely_pathogenic=1, Pathogenic=2, not_provided=1}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.17950329).. Strength limited to SUPPORTING due to the PP5.
• BS2: High AC in GnomAd at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPD1L	NM_015141.4	c.839C>T	p.Ala280Val	missense_variant	6/8	ENST00000282541.10
GPD1L	XM_006713068.3	c.698C>T	p.Ala233Val	missense_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPD1L	ENST00000282541.10	c.839C>T	p.Ala280Val	missense_variant	6/8	1	NM_015141.4	P1
GPD1L	ENST00000474846.5	n.763C>T		non_coding_transcript_exon_variant	1/3	2
GPD1L	ENST00000496151.1	n.340C>T		non_coding_transcript_exon_variant	1/3	2
GPD1L	ENST00000428684.1	c.*466C>T		3_prime_UTR_variant, NMD_transcript_variant	5/6	5

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000137 AC: 34 AN: 248254 Hom.: 0 AF XY: 0.000185 AC XY: 25 AN XY: 134790

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000207

Gnomad OTH exome AF: 0.000655

GnomAD4 exome AF: 0.0000801 AC: 117 AN: 1461050 Hom.: 1 Cov.: 34 AF XY: 0.000103 AC XY: 75 AN XY: 726864

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000702

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152316 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74490

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000127 Hom.: 0

Bravo AF: 0.0000982

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000989 AC: 12

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:3 Uncertain:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Brugada syndrome 2 Pathogenic:1 Uncertain:3 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 12, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Nov 21, 2018	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jun 11, 2020	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 -
Pathogenic, flagged submission	literature only	OMIM	Nov 13, 2007	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Brugada syndrome (shorter-than-normal QT interval) Pathogenic:1

Likely pathogenic, flagged submission

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 10, 2019

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. -

Death in infancy Pathogenic:1

Pathogenic, flagged submission

clinical testing

Forensic Genetics Laboratory, Harris County Institute of Forensic Sciences

Mar 27, 2015

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 15, 2019

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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 01, 2023

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) -

Brugada syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 06, 2023

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. -

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Dept of Medical Biology, Uskudar University

Jan 08, 2024

Criteria: BP4 -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 05, 2022

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	21
Dann	Benign	0.23
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.55	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.070	N
MutationTaster	Benign	0.99	A
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	0.29	N
REVEL	Benign	0.16
Sift	Benign	0.83	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.73
MVP		0.57
MPC		0.40
ClinPred		0.0087	T
GERP RS		3.4
Varity_R		0.13
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs72552291; hg19: chr3-32200588;