rs770998550

Variant names:

• chr3-32106749-C-T
• rs770998550
• NM_015141.4:c.38C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_015141.4(GPD1L):​c.38C>T​(p.Ser13Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000142 in 1,405,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GPD1L NM_015141.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.03
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• Brugada syndrome 2

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Brugada syndrome 1

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.851

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPD1L	NM_015141.4	c.38C>T	p.Ser13Leu	missense_variant	Exon 1 of 8	ENST00000282541.10	NP_055956.1
GPD1L	XM_006713068.3	c.38C>T	p.Ser13Leu	missense_variant	Exon 1 of 7		XP_006713131.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPD1L	ENST00000282541.10	c.38C>T	p.Ser13Leu	missense_variant	Exon 1 of 8	1	NM_015141.4	ENSP00000282541.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000103 AC: 2 AN: 193614 AF XY: 0.0000185

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000118

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000117

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1405044 Hom.: 0 Cov.: 30 AF XY: 0.00000286 AC XY: 2 AN XY: 698662

African (AFR) AF: 0.00 AC: 0 AN: 29110

American (AMR) AF: 0.00 AC: 0 AN: 38766

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24304

East Asian (EAS) AF: 0.00 AC: 0 AN: 33718

South Asian (SAS) AF: 0.00 AC: 0 AN: 80224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51520

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5500

European-Non Finnish (NFE) AF: 9.22e-7 AC: 1 AN: 1084368

Other (OTH) AF: 0.0000174 AC: 1 AN: 57534

GnomAD4 genome Cov.: 33

Alfa AF: 0.000139 Hom.: 0

ExAC AF: 0.00000834 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Brugada syndrome Uncertain:1

Sep 01, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine with leucine at codon 13 of the GPD1L protein (p.Ser13Leu). The serine residue is moderately conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs770998550, ExAC 0.002%). This variant has not been reported in the literature in individuals affected with GPD1L-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	34
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.61	D;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Benign	0.59	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Pathogenic	3.4	M;.
PhyloP100		4.0
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-4.8	D;D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.77
MutPred		0.73		Loss of glycosylation at S13 (P = 0.0096);Loss of glycosylation at S13 (P = 0.0096);
MVP		0.81
MPC		0.92
ClinPred		1.0	D
GERP RS		4.4
PromoterAI		-0.0026	Neutral
Varity_R		0.97
gMVP		0.90
Mutation Taster		=59/41	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs770998550; hg19: chr3-32148241;