chr8-38253642-G-C
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_015214.3(DDHD2):c.1978G>C(p.Asp660His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000133 in 1,614,104 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_015214.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000657 AC: 10AN: 152206Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000597 AC: 15AN: 251466Hom.: 0 AF XY: 0.0000662 AC XY: 9AN XY: 135908
GnomAD4 exome AF: 0.000140 AC: 204AN: 1461780Hom.: 0 Cov.: 31 AF XY: 0.000117 AC XY: 85AN XY: 727192
GnomAD4 genome AF: 0.0000656 AC: 10AN: 152324Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74486
ClinVar
Submissions by phenotype
Hereditary spastic paraplegia 54 Pathogenic:8
This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PM2,PP3,PP5. -
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Variant summary: DDHD2 c.1978G>C (p.Asp660His) results in a non-conservative amino acid change located in the DDHD domain (IPR004177) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 251466 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1978G>C has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Hereditary Spastic Paraplegia 54, and the variant was shown to segregate with disease in related individuals (e.g., Schuurs-Hoeijmakers_2012, Citterio_2015). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 24337409, 23176823). Six ClinVar submitters (evaluation after 2014) have cited the variant, and all submitters classified the variant as pathogenic (n = 4) or likely pathogenic (n = 2). Based on the evidence outlined above, the variant was classified as pathogenic. -
This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 660 of the DDHD2 protein (p.Asp660His). This variant is present in population databases (rs375168720, gnomAD 0.01%). This missense change has been observed in individual(s) with hereditary spastic paraplegia with thin corpus callosum (PMID: 23176823, 24337409, 24517879). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 39679). 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 DDHD2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects DDHD2 function (PMID: 25417924). For these reasons, this variant has been classified as Pathogenic. -
This missense variant leads to the substitution of a highly conserved aspartic acid (found in 12 species) within the DDHD domain of the DDHD2 protein with histidine. Amino acid alignments were generated using Alamut® Visual v.2.15 software (Interactive Biosoftware, SOPHiA GENETICS). This variant is predicted to be disease-causing by standard in silico prediction tools (CADD, SIFT, PolyPhen-2, and MutationTaster). ClinVar contains an entry for this variant (Variation ID: 39679), it’s classified as pathogenic. This variant is not reported in the 1000 Genomes Project but is present at a low frequency in the gnomAD database [AF = 6.1e-5]. Complete co-segregation between the variant allele and the disease distribution was observed in the patients’ family. This variant was identified in the homozygous state in two affected siblings and was present in the heterozygous state in the unaffected parents. This variant is associated with the following publications: (PMID: 23176823, 24337409, 24517879, 30564185, 31302745, 25417924) -
not provided Pathogenic:2
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Published functional studies demonstrate a damaging effect; the D660H variant demonstrates a reduction in phospholipase A1 activity (Doi et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33084218, 25417924, 23176823, 24337409, 24517879, 31302745, 27535533) -
Inborn genetic diseases Pathogenic:1
The c.1978G>C (p.D660H) alteration is located in exon 16 (coding exon 15) of the DDHD2 gene. This alteration results from a G to C substitution at nucleotide position 1978, causing the aspartic acid (D) at amino acid position 660 to be replaced by a histidine (H). Based on data from gnomAD, the C allele has an overall frequency of 0.006% (18/282874) total alleles studied. The highest observed frequency was 0.011% (14/129178) of European (non-Finnish) alleles. This variant has been identified in the homozygous state and/or in conjunction with other DDHD2 variant(s) in individual(s) with features consistent with DDHD2-related spastic paraplegia, and segregated with disease in a family/families; in at least one instance, the variants were identified in trans (Schuurs-Hoeijmakers, 2012; Citterio, 2014; Magariello, 2014; Nicita, 2019). This amino acid position is highly conserved in available vertebrate species. In multiple assays testing DDHD2 function, this variant showed functionally abnormal results (Doi, 2014; Chou, 2023). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -
Generalized epilepsy;C0028754:Obesity;C0557874:Global developmental delay Pathogenic:1
The c.1978G>C (p.Asp660His) missense variant in the DDHD2 gene is previously reported in the literature and is expected to be causative of hereditary spastic paraplegia when present in the homozygous or compound heterozygous state. DDHD2 encodes a protein that makes up a subunit of the enzyme phospholipase A1 (PLA1). This variant has been reported in multiple affected individuals in the compound heterozygous or homozygous state and has been shown to segregate with disease in families. In vitro functional studies on cell lines with this variant demonstrated significantly reduced PLA1 activity when compared to that of wild type cell lines. This variant involves a highly conserved nucleotide and amino acid, and it is predicted to be damaging by PolyPhen-2, SIFT, and MutationTaster. Therefore, based on prior reports in the literature and functional evidence, this variant is classified as pathogenic. -
Hereditary spastic paraplegia Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at