NM_001492.6:c.681C>A

Variant names:

• chr19-18869035-G-T
• rs121434422
• NM_001492.6:c.681C>A

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.681C>A​(p.Cys227*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000943 in 1,073,414 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00054 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (0 hom.)
• Consequence: GDF1 NM_001492.6 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16
• Conservation: PhyloP100: -0.0420
• Publications: 7 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 16 pathogenic variants in the truncated region.
• PP5: Variant 19-18869035-G-T is Pathogenic according to our data. Variant chr19-18869035-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 6747.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001492.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDF1	NM_001492.6	MANE Select	c.681C>A	p.Cys227*	stop_gained	Exon 8 of 8	NP_001483.3
	CERS1	NM_021267.5	MANE Select	c.*950C>A		3_prime_UTR	Exon 8 of 8	NP_067090.1
	GDF1	NM_001387438.1		c.681C>A	p.Cys227*	stop_gained	Exon 5 of 5	NP_001374367.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDF1	ENST00000247005.8	TSL:1 MANE Select	c.681C>A	p.Cys227*	stop_gained	Exon 8 of 8	ENSP00000247005.5
	CERS1	ENST00000623882.4	TSL:1 MANE Select	c.*950C>A		3_prime_UTR	Exon 8 of 8	ENSP00000485308.1

Frequencies

GnomAD3 genomes AF: 0.000536 AC: 79 AN: 147314 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000146

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: 0.000918

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000967

Gnomad OTH AF: 0.000492

GnomAD2 exomes AF: 0.00 AC: 0 AN: 306 AF XY: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00101 AC: 933 AN: 926100 Hom.: 0 Cov.: 29 AF XY: 0.000995 AC XY: 433 AN XY: 435070

African (AFR) AF: 0.000172 AC: 3 AN: 17472

American (AMR) AF: 0.00 AC: 0 AN: 3626

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7656

East Asian (EAS) AF: 0.00 AC: 0 AN: 10490

South Asian (SAS) AF: 0.00 AC: 0 AN: 18334

European-Finnish (FIN) AF: 0.00173 AC: 21 AN: 12150

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2080

European-Non Finnish (NFE) AF: 0.00108 AC: 887 AN: 821586

Other (OTH) AF: 0.000673 AC: 22 AN: 32706

GnomAD4 genome AF: 0.000536 AC: 79 AN: 147314 Hom.: 0 Cov.: 33 AF XY: 0.000544 AC XY: 39 AN XY: 71724

African (AFR) AF: 0.000146 AC: 6 AN: 40986

American (AMR) AF: 0.00 AC: 0 AN: 14830

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3390

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.000918 AC: 8 AN: 8712

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.000967 AC: 64 AN: 66158

Other (OTH) AF: 0.000492 AC: 1 AN: 2032

Alfa AF: 0.00115 Hom.: 0

Bravo AF: 0.000465

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Right atrial isomerism Pathogenic:5

Sep 03, 2024

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.681C>A p.(Cys227Ter) is a nonsense variant in the last exon of GDF1, that likely evades nonsense-mediated mRNA decay (NMD). This variant was found in a compound heterozygous state. Biallelic GDF1 variants are linked to autosomal recessive right atrial isomerism (OMIM #208530). This phenotype is compatible with the clinical presentation of our patient. This variant is not present in the homozygous state in population database gnomAD (v4.1.0). This variant was previously reported in a compound heterozygous state in patients with right atrial isomerism (PMID : 14648004, 20413652, 28991257). It has been reported as pathogenic or likely pathogenic multiple times in ClinVar. Based on the evidence outlined above, the variant was classified as pathogenic.

Oct 06, 2022

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 20, 2023

Institute of Human Genetics, Heidelberg University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Institute of Human Genetics, Medical University Innsbruck

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 15, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

not provided Pathogenic:4

Dec 06, 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.Cys227*) in the GDF1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 146 amino acid(s) of the GDF1 protein. This variant is present in population databases (rs121434422, gnomAD 0.09%). This premature translational stop signal has been observed in individual(s) with heterotaxy syndrome (PMID: 20413652). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6747). This variant disrupts the p.Cys277 amino acid residue in GDF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17924340, 17936261, 20413652). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Nov 22, 2023

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 27, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation, as the last 146 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 29429572, 32144877, 30679813, 34313030, 26258520, 18375573, 20497191, 19553149, 14648004, 20413652, 28991257, 34328347, 17924340)

Mar 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GDF1: PVS1:Strong, PM1, PM2, PM3

Congenital heart defects, multiple types, 6;C3178806:Right atrial isomerism Pathogenic:3

Sep 24, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

May 01, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 07, 2025

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The GDF1 c.681C>A (p.Cys227*) variant has been reported in a heterozygous individual affected with transposition of the great arteries (Karkera JD et al., PMID: 17924340) and as a compound heterozygous variant in patients with congenital heart disease, including five siblings with right atrial isomerism who harbored a pathogenic variant in trans (Jin SC et al., PMID: 28991257; Kaasinen E et al., PMID: 20413652). Of note, the father of the affected siblings who harbored the c.681C>A (p.Cys227*) variant was considered healthy (Kaasinen E et al., PMID: 20413652). This variant causes a premature stop codon; however, because this occurs in the last exon, this is not predicted to lead to nonsense mediated decay. The highest population minor allele frequency in the population database genome aggregation database (v.4.1) is 0.14% in the European Finnish population. This variant has been reported in the ClinVar database as a germline pathogenic or likely pathogenic variant by eleven submitters (ClinVar Variation ID: 6747). Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as likely pathogenic.

GDF1-related disorder Pathogenic:1

Jun 21, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The GDF1 c.681C>A variant is predicted to result in premature protein termination (p.Cys227*). This variant has previously been reported in the heterozygous state in an individual with transposition of the great arteries (Kakera et al. 2007. PubMed ID: 17924340). This variant was also reported in an individual with conotruncal defects. The variant was inherited; however, the phenotype of the parents was not provided (Patient 1-05514 - Table S1/S7 - Jin et al. 2017. PubMed ID: 28991257). In the compound heterozygous state this variant was found in five siblings with right atrial isomerism (Kaasinen et al. 2010. PubMed ID: 20413652) and an individual with heterotaxy (Patient 1-05386 - Table S1/S3 - Jin et al. 2017. PubMed ID: 28991257). The parents of the five siblings with right atrial isomerism were reported to be unaffected (Kaasinen et al. 2010. PubMed ID: 20413652). Of note, this variant is in 13 out of 25,686 alleles (~0.05%) in the gnomAD database; however, this may not be accurate due to low sequence coverage in this region. Nonsense variants in GDF1 are expected to be pathogenic for autosomal recessive disease; however, their role in autosomal dominant disease is uncertain. This variant is interpreted as pathogenic.

GDF1-RELATED DISORDERS Pathogenic:1

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This nonsense variant is found in the last exon of GDF1 and is therefore predicted to escape nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a heterozygous change in an individual with transposition of the great arteries (PMID: 17924340), and as a compound heterozygous change in patients with cardiac defects (PMID: 20413652, 28991257), including five siblings with right atrial isomerism, who harbored a frameshift variant on the opposite GDF1 allele; the parent who was heterozygous for the p.Cys227Ter variant was unaffected (PMID: 20413652). Heterozygous loss-of-function mutations in GDF1 are a known mechanism of cardiac defects ranging from tetralogy of Fallot to transposition of the great arteries (PMID: 17924340, 28991257, 23410880). The c.681C>A (p.Cys227Ter) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.05% (13/25686) and thus is presumed to be rare. Based on the available evidence, the c.681C>A (p.Cys227Ter) variant is classified as Likely Pathogenic.

Congenital heart defects, multiple types, 6 Pathogenic:1

Oct 19, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as 5-pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with right atrial isomerism (MIM#208530). Although loss of function has been demonstrated for missense variants, there is currently limited evidence demonstrating loss of function for truncating variants (PMIDs: 1792434; 20413652). (I) 0106 - This gene is associated with autosomal recessive disease. This gene has also been associated right atrial isomerism (Ivemark) (RAI) (MIM#208530) and congenital heart defects, multiple types, 6 (MIM#613854) (OMIM; PMID: 28991257) (I) 0204 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with at least 1/3 of the protein sequence affected. This variant might also affect the production of active protein although there is currently no functional evidence demonstrating this (PMID: 1792434; 20413652). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (13 heterozygotes, 0 homozygotes). (SP) 0702 - Other protein truncating variants comparable to the one identified in this case have strong previous evidence for pathogenicity. There are two protein truncating variants downstream of our variant of interest (ClinVar, Decipher). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been identified in 4 unrelated individuals with right atrial isomerism (MIM#208530) and a single patient with congenital heart defect (MIM#613854) (ClinVar, PMIDs: 1792434, 20413652, 32144877). (SP) 0901 - This variant has strong evidence for segregation with disease. This variant has been shown to segregate with disease in one family with five individuals diagnosed with right atrial isomerism (MIM#208530) (PMID: 20413652). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1101 - Very strong and specific phenotype match for this individual's fetus. (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (c.1047_1050delCTTT; p.(Phe349Leufs*35)) in a recessive disease (reported by Invitae #RQ1502139). (SP) 1205 - This variant has been shown to be paternally inherited in the fetus with symptoms consistent with congenital heart defects or heterotaxy (reported by Invitae #RQ1502139). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Transposition of the great arteries Pathogenic:1

Jul 15, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	32
DANN	Benign	0.96
Eigen	Benign	-0.67
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.024	N
PhyloP100		-0.042
Vest4		0.57
GERP RS		-2.4
Mutation Taster		=51/149	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121434422; hg19: chr19-18979844;