rs28938174
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PM5PP3_ModeratePP5
The NM_001360.3(DHCR7):c.356A>T(p.His119Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000143 in 1,613,796 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H119R) has been classified as Uncertain significance.
Frequency
Consequence
NM_001360.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DHCR7 | NM_001360.3 | c.356A>T | p.His119Leu | missense_variant | 5/9 | ENST00000355527.8 | |
DHCR7 | NM_001163817.2 | c.356A>T | p.His119Leu | missense_variant | 5/9 | ||
DHCR7 | XM_011544777.3 | c.356A>T | p.His119Leu | missense_variant | 5/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DHCR7 | ENST00000355527.8 | c.356A>T | p.His119Leu | missense_variant | 5/9 | 1 | NM_001360.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152078Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 250946Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135606
GnomAD4 exome AF: 0.0000151 AC: 22AN: 1461718Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9AN XY: 727142
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152078Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74260
ClinVar
Submissions by phenotype
Smith-Lemli-Opitz syndrome Pathogenic:3
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 1998 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 11, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 02, 2022 | This variant is present in population databases (rs28938174, gnomAD 0.0009%). This sequence change replaces histidine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 119 of the DHCR7 protein (p.His119Leu). This missense change has been observed in individual(s) with Smith-Lemli-Opitz syndrome (PMID: 9683613). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DHCR7 protein function. ClinVar contains an entry for this variant (Variation ID: 6780). - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 22, 2016 | The H119L missense pathogenic variant has been reported previously in association with SLOS (Witsch-Baumgartner et al., 2001). - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 17, 2024 | Variant summary: DHCR7 c.356A>T (p.His119Leu) results in a non-conservative amino acid change in 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 4e-06 in 250946 control chromosomes (gnomAD). c.356A>T has been reported in the literature in individuals affected with Smith-Lemli-Opitz Syndrome (Waterham_1998, Witsch-Baumgartner_2001). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 9683613, 11175299). ClinVar contains an entry for this variant (Variation ID: 6780). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at