12-56929515-A-G
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_148897.3(SDR9C7):c.599T>C(p.Ile200Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000049 in 1,612,366 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_148897.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152146Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251232Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135760
GnomAD4 exome AF: 0.0000507 AC: 74AN: 1460220Hom.: 0 Cov.: 31 AF XY: 0.0000551 AC XY: 40AN XY: 726042
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152146Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74316
ClinVar
Submissions by phenotype
Ichthyosis, congenital, autosomal recessive 13 Pathogenic:2
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SDR9C7-related disorder Pathogenic:1
The SDR9C7 c.599T>C variant is predicted to result in the amino acid substitution p.Ile200Thr. This variant was reported in the homozygous multiple related individuals with ichthyosis and was found to segregate with disease (Shigehara et al. 2016. PubMed ID: 28173123). In addition, the p.Ile200Thr change was found to be associated with reduced SDR9C7 protein expression in the cornified layer of the epidermis (Shigehara et al. 2016. PubMed ID: 28173123). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-57323299-A-G). This variant is interpreted as likely pathogenic. -
Lamellar ichthyosis Pathogenic:1
Variant summary: SDR9C7 c.599T>C (p.Ile200Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251232 control chromosomes. c.599T>C has been reported in the literature in multiple homozygous or compound heterozygous individuals affected with Lamellar Ichthyosis (Shigehara_2016, Seidl-Philipp_2019). These data indicate that the variant is very likely to be associated with disease. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Shigehara_2016). The following publications have been ascertained in the context of this evaluation (PMID: 31012992, 28173123). ClinVar contains an entry for this variant (Variation ID: 430711). Based on the evidence outlined above, the variant was classified as pathogenic. -
not provided Pathogenic:1
Segregates with disease in many affected individuals from multiple families in the published literature (PMID: 28173123, 31012992); Published functional studies demonstrate significantly reduced protein expression in vitro (PMID: 28173123); 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: 27538420, 31012992, 28173123) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at