19-18868806-CG-CGG

Variant names:

• chr19-18868806-C-CG
• rs606231383
• NM_001492.6:c.909dupC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_Strong PP5_Very_Strong

The NM_001492.6(GDF1):​c.909dupC​(p.Val304ArgfsTer48) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000105 in 1,454,670 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000093 (0 hom.)
• Consequence: GDF1 NM_001492.6 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: -0.683
• Publications: 2 publications found

Genes affected

GDF1 (HGNC:4214): (growth differentiation factor 1) This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate each subunit of the disulfide-linked homodimer. Studies in rodents suggest that this protein is involved in the establishment of left-right asymmetry in early embryogenesis and in neural development in later embryogenesis. The encoded protein is translated from a bicistronic mRNA that also encodes ceramide synthase 1. Mutations in this gene are associated with several congenital cardiovascular malformations. [provided by RefSeq, Jul 2016]

CERS1 (HGNC:14253): (ceramide synthase 1) This gene encodes a ceramide synthase enzyme, which catalyzes the synthesis of ceramide, the hydrophobic moiety of sphingolipids. The encoded enzyme synthesizes 18-carbon (C18) ceramide in brain neurons. Elevated expression of this gene may be associated with increased longevity, while decreased expression of this gene may be associated with myoclonus epilepsy with dementia in human patients. This protein is transcribed from a monocistronic mRNA as well as a bicistronic mRNA, which also encodes growth differentiation factor 1. [provided by RefSeq, Jul 2016]

CERS1 Gene-Disease associations (from GenCC):

• progressive myoclonic epilepsy type 8

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 8 pathogenic variants in the truncated region.
• PP5: Variant 19-18868806-C-CG is Pathogenic according to our data. Variant chr19-18868806-C-CG is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 65389.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GDF1	NM_001492.6	c.909dupC	p.Val304ArgfsTer48	frameshift_variant	Exon 8 of 8	ENST00000247005.8	NP_001483.3
CERS1	NM_021267.5	c.*1178dupC		3_prime_UTR_variant	Exon 8 of 8	ENST00000623882.4	NP_067090.1
GDF1	NM_001387438.1	c.909dupC	p.Val304ArgfsTer48	frameshift_variant	Exon 5 of 5		NP_001374367.1
CERS1	NM_001387440.1	c.*1770dupC		3_prime_UTR_variant	Exon 7 of 7		NP_001374369.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GDF1	ENST00000247005.8	c.909dupC	p.Val304ArgfsTer48	frameshift_variant	Exon 8 of 8	1	NM_001492.6	ENSP00000247005.5
CERS1	ENST00000623882.4	c.*1178dupC		3_prime_UTR_variant	Exon 8 of 8	1	NM_021267.5	ENSP00000485308.1

Frequencies

GnomAD3 genomes AF: 0.000215 AC: 32 AN: 148968 Hom.: 0 Cov.: 33

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: 0.00160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000255

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000213 AC: 24 AN: 112872 AF XY: 0.000242

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00159

Gnomad NFE exome AF: 0.000102

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000927 AC: 121 AN: 1305702 Hom.: 0 Cov.: 31 AF XY: 0.000101 AC XY: 65 AN XY: 644450

African (AFR) AF: 0.00 AC: 0 AN: 25762

American (AMR) AF: 0.00 AC: 0 AN: 30826

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21326

East Asian (EAS) AF: 0.00 AC: 0 AN: 26364

South Asian (SAS) AF: 0.00 AC: 0 AN: 75774

European-Finnish (FIN) AF: 0.00103 AC: 44 AN: 42796

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4462

European-Non Finnish (NFE) AF: 0.0000701 AC: 72 AN: 1026530

Other (OTH) AF: 0.0000964 AC: 5 AN: 51862

GnomAD4 genome AF: 0.000215 AC: 32 AN: 148968 Hom.: 0 Cov.: 33 AF XY: 0.000275 AC XY: 20 AN XY: 72610

African (AFR) AF: 0.00 AC: 0 AN: 41124

American (AMR) AF: 0.00 AC: 0 AN: 14994

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3408

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00160 AC: 15 AN: 9358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000255 AC: 17 AN: 66794

Other (OTH) AF: 0.00 AC: 0 AN: 2058

Alfa AF: 0.00124 Hom.: 0

Bravo AF: 0.0000227

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Right atrial isomerism Pathogenic:2

Jul 15, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

Institute of Human Genetics, Medical University Innsbruck

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2

Sep 28, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Val304Argfs*48) in the GDF1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 69 amino acid(s) of the GDF1 protein. This variant is present in population databases (rs606231383, gnomAD 0.1%). This premature translational stop signal has been observed in individual(s) with clinical features of GDF1-related conditions and/or right atrial isomerism (PMID: 20413652, 34486251). It has also been observed to segregate with disease in related individuals. This variant is also known as c.909insC. ClinVar contains an entry for this variant (Variation ID: 65389). For these reasons, this variant has been classified as Pathogenic. -

Jun 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GDF1: PVS1:Strong, PM2 -

Congenital heart defects, multiple types, 6;C3178806:Right atrial isomerism Pathogenic:1

May 01, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.68
Mutation Taster		=32/168	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs606231383; hg19: chr19-18979615;