chr19-18868665-CAAAG-C

Position:

• chr19-18868665-CAAAG-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_Moderate PP5_Very_Strong

The NM_001492.6(GDF1):​c.1047_1050del​(p.Phe349LeufsTer35) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000953 in 1,574,596 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: GDF1 NM_001492.6 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 3.76

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 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. Fraction of 0.0643 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PP5: Variant 19-18868665-CAAAG-C is Pathogenic according to our data. Variant chr19-18868665-CAAAG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 410641.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-18868665-CAAAG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GDF1	NM_001492.6	c.1047_1050del	p.Phe349LeufsTer35	frameshift_variant	8/8	ENST00000247005.8
CERS1	NM_021267.5	c.*1316_*1319del		3_prime_UTR_variant	8/8	ENST00000623882.4
GDF1	NM_001387438.1	c.1047_1050del	p.Phe349LeufsTer35	frameshift_variant	5/5
CERS1	NM_001387440.1	c.*1908_*1911del		3_prime_UTR_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GDF1	ENST00000247005.8	c.1047_1050del	p.Phe349LeufsTer35	frameshift_variant	8/8	1	NM_001492.6	P1
CERS1	ENST00000623882.4	c.*1316_*1319del		3_prime_UTR_variant	8/8	1	NM_021267.5	P2

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152088 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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000651 AC: 12 AN: 184466 Hom.: 0 AF XY: 0.0000502 AC XY: 5 AN XY: 99680

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000211

Gnomad SAS exome AF: 0.0000404

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000782

Gnomad OTH exome AF: 0.000411

GnomAD4 exome AF: 0.000101 AC: 143 AN: 1422508 Hom.: 0 AF XY: 0.000101 AC XY: 71 AN XY: 703908

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000106

Gnomad4 SAS exome AF: 0.0000616

Gnomad4 FIN exome AF: 0.0000607

Gnomad4 NFE exome AF: 0.000114

Gnomad4 OTH exome AF: 0.000119

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152088 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74300

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: 0.000103

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000680

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 23, 2018	The c.1047_1050delCTTT variant in the GDF1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.1047_1050delCTTT variant causes a frameshift starting with codon Phenylalanine 349, changes this amino acid to a Leucine residue, and creates a premature Stop codon at position 35 of the new reading frame, denoted p.Phe349LeufsX35. This frameshift variant replaces the typical last 24 amino acid residues in the GDF1 protein with 34 different amino acid residues, which is predicted to cause loss of normal protein function. The c.1047_1050delCTTT variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret c.1047_1050delCTTT as a likely pathogenic variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	May 03, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 05, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 410641). This premature translational stop signal has been observed in individual(s) with heterotaxy (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs768027510, gnomAD 0.02%). This sequence change creates a premature translational stop signal (p.Phe349Leufs*35) in the GDF1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 24 amino acid(s) of the GDF1 protein. -

Congenital heart defects, multiple types, 6 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jan 25, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 19, 2020	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Likely 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 been associated right atrial isomerism (Ivemark) (RAI) (MIM#208530) and congenital heart defects, multiple types, 6 (MIM#613854) (OMIM; PMID: 28991257). (I) 0208 - Variant is predicted to result in an elongated protein. (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (14 heterozygotes, 0 homozygotes). (SP) 0600 - Variant is located in the annotated TGF-beta like domain (NCBI conserved domain). (I) 0705 - No comparable protein truncating variants have previous evidence for pathogenicity. (I) 0803 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported in 3 unrelated individuals from clinical testing laboratories (ClinVar). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 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.681C>A; p.(Cys227*)) in a recessive disease (reported by Invitae #RQ1502139). (SP) 1205 - This variant has been shown to be maternally inherited in her fetus with symptoms consistent with congenital heart defects or heterotaxy (reported by Invitae #RQ1502139). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

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: rs768027510; hg19: chr19-18979474;