chr19-18868625-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 13P and 1B. PM1PM5PP3PP5_Very_StrongBP4

The NM_001492.6(GDF1):ā€‹c.1091T>Cā€‹(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 (ā˜…ā˜…). 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: š‘“ 0.00028 ( 0 hom., cov: 33)
Exomes š‘“: 0.00020 ( 0 hom. )

Consequence

GDF1
NM_001492.6 missense

Scores

9
7
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 7.14
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]
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 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 6: AlphaMissense, Cadd, M_CAP, MutationAssessor, PROVEAN, 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/exons MANE UniProt
GDF1NM_001492.6 linkuse as main transcriptc.1091T>C p.Met364Thr missense_variant 8/8 ENST00000247005.8
CERS1NM_021267.5 linkuse as main transcriptc.*1360T>C 3_prime_UTR_variant 8/8 ENST00000623882.4
GDF1NM_001387438.1 linkuse as main transcriptc.1091T>C p.Met364Thr missense_variant 5/5
CERS1NM_001387440.1 linkuse as main transcriptc.*1952T>C 3_prime_UTR_variant 7/7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GDF1ENST00000247005.8 linkuse as main transcriptc.1091T>C p.Met364Thr missense_variant 8/81 NM_001492.6 P1
CERS1ENST00000623882.4 linkuse as main transcriptc.*1360T>C 3_prime_UTR_variant 8/81 NM_021267.5 P2P27544-1

Frequencies

GnomAD3 genomes
AF:
0.000276
AC:
42
AN:
152086
Hom.:
0
Cov.:
33
show subpopulations
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
GnomAD3 exomes
AF:
0.000508
AC:
93
AN:
182990
Hom.:
0
AF XY:
0.000526
AC XY:
52
AN XY:
98798
show subpopulations
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 SAS 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
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000512
Gnomad4 ASJ exome
AF:
0.00771
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000367
Gnomad4 OTH exome
AF:
0.000852
GnomAD4 genome
AF:
0.000276
AC:
42
AN:
152086
Hom.:
0
Cov.:
33
AF XY:
0.000310
AC XY:
23
AN XY:
74296
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.0101
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000735
Gnomad4 OTH
AF:
0.000479
Alfa
AF:
0.000998
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:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:3
Likely pathogenic, criteria provided, single submitterclinical testingGeneDxJun 14, 2022In 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) -
Likely pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 08, 2023In 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GDF1 protein function. ClinVar contains an entry for this variant (Variation ID: 522571). 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). This variant is present in population databases (rs374016704, gnomAD 0.9%), and has an allele count higher than expected for a pathogenic variant. 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). -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenFeb 01, 2020- -
Heart, malformation of Pathogenic:1
Likely pathogenic, no assertion criteria providedcurationReproductive Health Research and Development, BGI GenomicsJan 06, 2020NM_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, 6 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMApr 18, 2018- -

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;.
MutationTaster
Benign
1.0
D;D
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

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs374016704; hg19: chr19-18979434; API