chr17-2036050-T-C
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_001383.6(DPH1):c.359T>C(p.Leu120Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000496 in 1,613,970 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_001383.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000289 AC: 44AN: 152124Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000289 AC: 72AN: 248874Hom.: 0 AF XY: 0.000333 AC XY: 45AN XY: 135294
GnomAD4 exome AF: 0.000517 AC: 756AN: 1461728Hom.: 0 Cov.: 31 AF XY: 0.000495 AC XY: 360AN XY: 727186
GnomAD4 genome AF: 0.000289 AC: 44AN: 152242Hom.: 0 Cov.: 32 AF XY: 0.000255 AC XY: 19AN XY: 74434
ClinVar
Submissions by phenotype
Developmental delay with short stature, dysmorphic facial features, and sparse hair Pathogenic:4
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The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.029%). Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 30877278). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.73; 3Cnet: 3CNET). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000521028). The variant has been reported to co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID: 30877278). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
PS3, PM3 -
Developmental delay with short stature, dysmorphic facial features, and sparse hair 1 Pathogenic:2
Variant summary: DPH1 c.359T>C (p.Leu120Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 248874 control chromosomes. This frequency does not allow conclusion about variant significance. c.359T>C has been reported in the literature in 2 homozygous siblings affected with Developmental Delay With Short Stature, Dysmorphic Facial Features, And Sparse Hair 1 (Lefebvre_2021, Urreizti_2020) . These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function demonstrating reduced amounts of ADP-ribosylated eEF2 (Urreizti_2020). The following publications have been ascertained in the context of this evaluation (PMID: 32732226, 30877278). ClinVar contains an entry for this variant (Variation ID: 521028). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
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Inborn genetic diseases Pathogenic:1
The c.374T>C (p.L125P) alteration is located in coding exon 4 of the DPH1 gene. This alteration results from a T to C substitution at nucleotide position 374, causing the leucine (L) at amino acid position 125 to be replaced by a proline (P). Based on data from gnomAD, the C allele has an overall frequency of 0.029% (80/280222) total alleles studied. The highest observed frequency was 0.059% (21/35334) of Latino alleles. This variant has been identified in the homozygous state and/or in conjunction with other DPH1 variant(s) in individual(s) with features consistent with DPH1-related neurodevelopmental disorder (Ambry internal data; Urreizti, 2020; Lefebvre, 2021; Faas, 2023; Drexler, 2023). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -
DPH1-related disorder Pathogenic:1
The DPH1 c.374T>C variant is predicted to result in the amino acid substitution p.Leu125Pro. This variant in the homozygous state has been reported in a neonatal patient who was diagnosed with structural anomalies such as birth defects, dysmorphic features, cardiac, craniofacial, and skeletal defects (Powis et al. 2018. PubMed ID: 29565416, Supplementary Table 1). This variant was also reported in the homozygous state in two siblings presenting with a variety of features including developmental delay, central nervous system malformations, short stature, unusual skull shape, and genital anomalies (Urreizti et al. 2020. PubMed ID: 30877278), and a fetus with multiple congenital abnormalities (Lefebvre et al. 2021. PubMed ID: 32732226). Functional studies of DPH1 p.Leu125Pro showed reduced enzyme activity (Urreizti et al. 2020. PubMed ID: 30877278). This variant is reported in 0.059% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as likely pathogenic. -
not provided Pathogenic:1
Published functional studies demonstrate a damaging effect of reduced ADP-ribosylated eEF2 (PMID: 30877278); 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: 26220823, 25558065, 29565416, 24895408, 14744934, 30877278, 32732226, 34297361, 27460824, 26415585, 33704902, 37675463, 36647814, 37326029) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at