chr19-18868625-A-G

Variant names:

• chr19-18868625-A-G
• rs374016704
• NM_001492.6:c.1091T>C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 13P and 1B. PM1 PM5 PP3 PP5_Very_Strong BP4

The NM_001492.6(GDF1):​c.1091T>C​(p.Met364Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000209 in 1,571,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M364I) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: GDF1 NM_001492.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 7.14

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

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

• PM1: In a chain Embryonic growth/differentiation factor 1 (size 118) in uniprot entity GDF1_HUMAN there are 7 pathogenic changes around while only 2 benign (78%) in NM_001492.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-18868624-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1507891.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, Cadd, M_CAP, MutationAssessor, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• PP5: Variant 19-18868625-A-G is Pathogenic according to our data. Variant chr19-18868625-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 522571.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0835813). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GDF1	NM_001492.6	c.1091T>C	p.Met364Thr	missense_variant	Exon 8 of 8	ENST00000247005.8	NP_001483.3
CERS1	NM_021267.5	c.*1360T>C		3_prime_UTR_variant	Exon 8 of 8	ENST00000623882.4	NP_067090.1
GDF1	NM_001387438.1	c.1091T>C	p.Met364Thr	missense_variant	Exon 5 of 5		NP_001374367.1
CERS1	NM_001387440.1	c.*1952T>C		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.1091T>C	p.Met364Thr	missense_variant	Exon 8 of 8	1	NM_001492.6	ENSP00000247005.5
CERS1	ENST00000623882	c.*1360T>C		3_prime_UTR_variant	Exon 8 of 8	1	NM_021267.5	ENSP00000485308.1

Frequencies

GnomAD3 genomes AF: 0.000276 AC: 42 AN: 152086 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000508 AC: 93 AN: 182990 AF XY: 0.000526

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000708

Gnomad ASJ exome AF: 0.00889

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000105

Gnomad OTH exome AF: 0.00104

GnomAD4 exome AF: 0.000202 AC: 287 AN: 1419596 Hom.: 0 Cov.: 31 AF XY: 0.000212 AC XY: 149 AN XY: 702218

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 32594

Gnomad4 AMR exome AF: 0.0000512 AC: 2 AN: 39040

Gnomad4 ASJ exome AF: 0.00771 AC: 195 AN: 25286

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 37500

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 80780

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 49176

Gnomad4 NFE exome AF: 0.0000367 AC: 40 AN: 1090836

Gnomad4 Remaining exome AF: 0.000852 AC: 50 AN: 58670

GnomAD4 genome AF: 0.000276 AC: 42 AN: 152086 Hom.: 0 Cov.: 33 AF XY: 0.000310 AC XY: 23 AN XY: 74296

Gnomad4 AFR AF: 0.0000241 AC: 0.0000241406 AN: 0.0000241406

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.0101 AC: 0.0100865 AN: 0.0100865

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000735 AC: 0.0000735489 AN: 0.0000735489

Gnomad4 OTH AF: 0.000479 AC: 0.000478927 AN: 0.000478927

Alfa AF: 0.00101 Hom.: 0

Bravo AF: 0.000306

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000360 AC: 3

ExAC AF: 0.000213 AC: 25

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Feb 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 364 of the GDF1 protein (p.Met364Thr). This variant is present in population databases (rs374016704, gnomAD 0.9%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with congenital heart disease and/or abnormality of the cardiovascular system (PMID: 26633542, 28991257, 34958143). It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 28991257). ClinVar contains an entry for this variant (Variation ID: 522571). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GDF1 protein function with a positive predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Jun 14, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31876989, 31818857, 26633542, 28991257, 31589614) -

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

May 08, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Heart, malformation of Pathogenic:1

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

NM_001492.4:c.1091T>C in the GDF1 gene has an allele frequency of 0.009 in Ashkenazi Jewish subpopulation in the gnomAD database. This variant has been reported to be a common cause of congenital heart disease in the Ashkenazi Jewish population and has been found in homozygosity in 10 affected individuals (PMID: 28991257). Additional evidence supports homozygosity for p.Met364Thr in CHD risk among Ashkenazim. p.Met364Thr shows remarkable violation of Hardy Weinberg equilibrium among Ashkenazi CHD cases, (P = 5.5x10-38, 1-df chi-square test with Yates correction). In contrast, among 302 Ashkenazi autism parental controls and 926 additional Ashkenazi adults from an independent cohort without CHD, there were no homozygotes and 12 heterozygotes (two-sided Fisher's Exact P = 2.8x10-9). Pathogenic computational verdict because pathogenic predictions from DANN, DEOGEN2, MutationTaster, REVEL and SIFTT. We interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PS4; PM3. -

Congenital heart defects, multiple types Pathogenic:1

Nov 19, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Pathogenic. Evidence in support of pathogenic classification: - Variant is present in gnomAD <0.01 (v4: 329 heterozygote(s), 0 homozygote(s)). - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been classified as pathogenic and likely pathogenic by multiple clinical laboratories in ClinVar, and has been reported in the literature in multiple unrelated homozygous individuals with congenital heart defects. It is suspected to be a founder mutation in the Ashkenazi Jewish population (PMID: 28991257). - Missense variant consistently predicted to be damaging by an in silico tool or highly conserved with a major amino acid change. Additional information: - Variant is predicted to result in a missense amino acid change from methionine to threonine. - This variant is homozygous. - This gene is associated with both recessive and dominant disease (OMIM). There is no clear association between variant type and disease inheritance pattern (PMID: 32144877). - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v4; highest allele count: 6 heterozygote(s), 0 homozygote(s)). - Loss of function is a known mechanism of disease in this gene and is associated with congenital heart defects, multiple types, 6 (MIM#613854) and right atrial isomerism (Ivemark) (MIM#208530). The majority of premature termination variants reported are associated with autosomal recessive inheritance; however, one was also reported for autosomal dominant inheritance (PMID: 32144877, 33131162). - Inheritance information for this variant is not currently available in this individual. -

Congenital heart defects, multiple types, 6 Pathogenic:1

Apr 18, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Uncertain	0.087	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D;.
M_CAP	Pathogenic	0.86	D
MetaRNN	Benign	0.084	T;T
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Pathogenic	3.3	M;.
PROVEAN	Pathogenic	-5.6	D;.
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Vest4		0.82
MVP		0.71
MPC		2.2
ClinPred		0.19	T
GERP RS		3.8
Varity_R		0.90
gMVP		0.93
Mutation Taster		=20/80	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs374016704; hg19: chr19-18979434;