rs751325113
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_032357.4(CCDC115):āc.92T>Cā(p.Leu31Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,613,698 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 Pathogenic (ā ā ).
Frequency
Consequence
NM_032357.4 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: 0.0000461 AC: 7AN: 151850Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.00000798 AC: 2AN: 250642Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135554
GnomAD4 exome AF: 0.0000226 AC: 33AN: 1461848Hom.: 0 Cov.: 33 AF XY: 0.0000206 AC XY: 15AN XY: 727232
GnomAD4 genome AF: 0.0000461 AC: 7AN: 151850Hom.: 0 Cov.: 31 AF XY: 0.0000540 AC XY: 4AN XY: 74124
ClinVar
Submissions by phenotype
CCDC115-CDG Pathogenic:4
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This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported in several patients with CCDC115 deficiency [PMID: 26833332] -
The p.Leu31Ser variant in CCDC115 has been reported in 3 homozygous and 4 compound heterozygous (3 of which carried a loss of function allele in trans and one individual carried a missense) individuals with congenital disorder of glycosylation and segregated with disease in 2 affected relatives from 1 family (Jansen 2016 PMID:26833332, Girard 2018 PMID: 29759592). This variant has been identified in 3/128322 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro and in vivo functional studies support an impact on protein function (Jansen 2016 PMID:26833332). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive congenital disorder of glycosylation. ACMG/AMP Criteria applied: PP3, PS3_Supporting, PP1_Supporting, PM3_Very Strong. -
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with congenital disorder of glycosylation, type IIo (CDG; MIM#616828). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from leucine to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 7 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3: 125 heterozygotes, 1 homozygote). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been identified in at least ten probands, both homozygotes and compound heterozygotes, diagnosed with CDG (PMIDs: 26833332, 29759592, 33413482). This variant has also been classified as pathogenic by diagnostic laboratories in ClinVar. (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
not provided Pathogenic:2
This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 31 of the CCDC115 protein (p.Leu31Ser). This variant is present in population databases (rs751325113, gnomAD 0.002%). This missense change has been observed in individual(s) with congenital disorder of glycosylation (PMID: 26833332, 29759592, 33413482). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 218967). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. -
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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: 26833332, 33413482, 29759592, 25902754) -
Congenital disorders of glycosylation type II Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at