rs72552291

Positions:

chr3-32159096-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000080 ( 1 hom. )

Consequence

GPD1L
NM_015141.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:9B:1O:1

Conservation

PhyloP100: 1.36

Variant links:

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]

GPD1L links:

GPD1L (HGNC:):

GPD1L links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.17950329).

BS2

High AC in GnomAd4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPD1L	NM_015141.4 linkuse as main transcript	c.839C>T	p.Ala280Val	missense_variant	6/8	ENST00000282541.10	NP_055956.1	Q8N335
GPD1L	XM_006713068.3 linkuse as main transcript	c.698C>T	p.Ala233Val	missense_variant	5/7		XP_006713131.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPD1L	ENST00000282541.10 linkuse as main transcript	c.839C>T	p.Ala280Val	missense_variant	6/8	1	NM_015141.4	ENSP00000282541.6		Q8N335

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

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:

AN:

248254

Hom.:

AF XY:

0.000185

AC XY:

AN XY:

134790

show subpopulations

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.:

Cov.:

AF XY:

0.000103

AC XY:

AN XY:

726864

show subpopulations

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:

AN:

152316

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74490

show subpopulations

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.:

Bravo

AF:

0.0000982

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000989

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:9Benign:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Brugada syndrome 2

Pathogenic:1Uncertain:3Other:1

Pathogenic, flagged submission	literature only	OMIM	Nov 13, 2007	- -
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 -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 12, 2020	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Brugada syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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. -
Uncertain significance, criteria provided, single submitter	research	Lildballe Lab, Aarhus University Hospital	Mar 01, 2024	PM2(s), BS2(s), PP5(noinf) -

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

- -

GPD1L-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 15, 2024

The GPD1L c.839C>T variant is predicted to result in the amino acid substitution p.Ala280Val. This variant was reported in individuals with Brugada syndrome, left ventricular hypertrabeculation, or sudden death (London et al. 2007. PubMed ID: 17967977; Table S1, Adle et al. 2016. PubMed ID: 26743238; Methner et al. 2016. PubMed ID: 27435932; Table S3, Miszalski-Jamka et al. 2017. PubMed ID: 28798025). Functional studies showed that this variant results in reduced enzyme activity, altered SCN5A channel surface expression, and reduces inward sodium current (London et al. 2007. PubMed ID: 17967977; Valdivia et al. 2009. PubMed ID: 19666841; Liu et al. 2009. PubMed ID: 19745168). However, this variant was also reported in unaffected individuals (Table S1, Chen et al. 2018. PubMed ID: 30662450; Campuzano et al. 2019. PubMed ID: 30821013) and documented to co-occur with additional variants which may explain clinical features (Table S3, Miszalski-Jamka et al. 2017. PubMed ID: 28798025; Table S15, Clark et al. 2019. PubMed ID: 31019026; Table S1, Ziats et al. 2020. PubMed ID: 31618753). This variant is reported in 0.020% of alleles in individuals of European (non-Finnish) descent in gnomAD and the majority of labs interpret this variant as uncertain in ClinVar (http://www.ncbi.nlm.nih.gov/clinvar/variation/786). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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) -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 09, 2024

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.23

DEOGEN2

Benign

0.23

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.55

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.017

MetaRNN

Benign

0.18

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.070

PrimateAI

Uncertain

0.65

PROVEAN

Benign

0.29

REVEL

Benign

0.16

Sift

Benign

0.83

Sift4G

Benign

1.0

Polyphen

0.0010

Vest4

0.73

MVP

0.57

MPC

0.40

ClinPred

0.0087

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over