chr19-18868665-CAAAG-C

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_ModeratePP5_Very_Strong

The NM_001492.6(GDF1):c.1047_1050delCTTT(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

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 3.76

Variant links:

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]

GDF1 links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 0 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 rank	MANE	Protein	UniProt
GDF1	NM_001492.6 link	c.1047_1050delCTTT	p.Phe349LeufsTer35	frameshift_variant	Exon 8 of 8	ENST00000247005.8	NP_001483.3	P27539A0A024R7N8
CERS1	NM_021267.5 link	c.1316_1319delCTTT		3_prime_UTR_variant	Exon 8 of 8	ENST00000623882.4	NP_067090.1	P27544-1
GDF1	NM_001387438.1 link	c.1047_1050delCTTT	p.Phe349LeufsTer35	frameshift_variant	Exon 5 of 5		NP_001374367.1
CERS1	NM_001387440.1 link	c.1908_1911delCTTT		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 link	c.1047_1050delCTTT	p.Phe349LeufsTer35	frameshift_variant	Exon 8 of 8	1	NM_001492.6	ENSP00000247005.5		P27539
CERS1	ENST00000623882 link	c.1316_1319delCTTT		3_prime_UTR_variant	Exon 8 of 8	1	NM_021267.5	ENSP00000485308.1		P27544-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152088

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:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000651

AC:

AN:

184466

Hom.:

AF XY:

0.0000502

AC XY:

AN XY:

99680

show subpopulations

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.:

AF XY:

0.000101

AC XY:

AN XY:

703908

show subpopulations

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:

AN:

152088

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74300

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:

0.000103

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000680

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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	Labcorp Genetics (formerly Invitae), Labcorp	Oct 15, 2024	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. This variant is present in population databases (rs768027510, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with heterotaxy (internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 410641). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	May 03, 2020	- -

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 -

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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 11, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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