rs757415879
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000094.4(COL7A1):c.5797C>T(p.Arg1933Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,666 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R1933R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000094.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL7A1 | NM_000094.4 | c.5797C>T | p.Arg1933Ter | stop_gained | 71/119 | ENST00000681320.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL7A1 | ENST00000681320.1 | c.5797C>T | p.Arg1933Ter | stop_gained | 71/119 | NM_000094.4 | P1 | ||
COL7A1 | ENST00000328333.12 | c.5797C>T | p.Arg1933Ter | stop_gained | 70/118 | 1 | P1 | ||
COL7A1 | ENST00000487017.5 | n.1714C>T | non_coding_transcript_exon_variant | 36/83 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152120Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461546Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1AN XY: 727058
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152120Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74320
ClinVar
Submissions by phenotype
Epidermolysis bullosa dystrophica Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | The COL7A1 c.5797C>T (p.Arg1933Ter) variant is a stop-gained variant reported in a total of ten individuals with dystrophic epidermolysis bullosa, including one homozygote, seven compound heterozygotes, two affected heterozygotes in whom a second variant was not identified, and in one unaffected heterozygous parent of an affected individual (Whittock et al. 1999; Csikos et al. 2003; Wessagowit et al. 2005; Kern et al. 2006; Arnold et al. 2009; Escamez et al. 2010; Montaudie et al. 2016). The variant was absent from 100 control individuals and from 192 control chromosomes (Csikos et al. 2005; Oh et al. 2007; Escamez et al. 2010). It is reported at a frequency of 0.00002 in the European (non-Finnish) population of the Exome Aggregation Consortium, but this is based on only one allele in a region of good sequence coverage, so it is presumed to be rare. Expression studies in HEK293 cells showed a complete lack of expression of the p.Arg1933Ter variant (Cogan et al. 2014). Based on the evidence, the p.Arg1933Ter variant is classified as pathogenic for dystrophic epidermolysis bullosa. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Recessive dystrophic epidermolysis bullosa Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Center for Research in Genodermatoses and Epidermolysis Bullosa, University of Buenos Aires | Mar 14, 2022 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 21, 2023 | This sequence change creates a premature translational stop signal (p.Arg1933*) in the COL7A1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL7A1 are known to be pathogenic (PMID: 16971478). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with autosomal recessive epidermolysis bullosa dystrophica (PMID: 10504458, 12653705, 15816848, 27544590, 29500833). ClinVar contains an entry for this variant (Variation ID: 345830). For these reasons, this variant has been classified as Pathogenic. - |
Epidermolysis bullosa dystrophica inversa, autosomal recessive Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
COL7A1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 13, 2023 | Variant summary: COL7A1 c.5797C>T (p.Arg1933X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic in ClinVar and reported in association with Epidermolysis bullosa dystrophica in HGMD. The variant was absent in 250778 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5797C>T has been reported in the literature in both compound heterozygous and homozygous individuals affected with Dystrophic Epidermolysis Bullosa, Recessive (e.g., Whittock_1999, Kern_2006). These data indicate that the variant is likely to be associated with disease. Four ClinVar submitters (evaluation after 2014) have cited the variant, and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at