ClinVar Genomic variation as it relates to human health

PS3, PM3

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.

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). The heterozygous missense change is ultra rare in healthy individuals:_x000D_ Based on data from the NHLBI Exome Sequencing Project (ESP), the DPH1 c.374T>C alteration was observed in 2 among 12,852 total alleles studied (0.02%). In the ExAC database, this alteration was observed in 29 among 119,540 total alleles studied (0.02%). Allele frequency data for this nucleotide position are not currently available from the 1000 Genomes Project. This variant is reported in the SNPDatabase as rs200530055. Rare missense alleles commonly exhibit a deleterious effect on protein function (Kryukov, 2007; Tennessen, 2012; please note that some variants may appear to be rare due to ethnic underrepresentation in the database). IF USED, PULL THESE INTO REFERENCES:_x000D_ Kryukov GV, et al. (2007) Am J Hum Genet 80:727-739. Tennessen JA, et al. (2012) Science 337(64):64-69. The altered amino acid is conserved throughout evolution:_x000D_ The p.L125 amino acid is conserved in available vertebrate species. The alteration is predicted deleterious by in silico models:_x000D_ The p.L125P alteration is predicted to be probably damaging by Polyphen and deleterious by SIFT in silico analyses. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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.

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)

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.