rs1203706188
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000094.4(COL7A1):c.409C>T(p.Arg137Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000041 in 1,461,870 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. R137R) 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 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL7A1 | NM_000094.4 | c.409C>T | p.Arg137Ter | stop_gained | 4/119 | ENST00000681320.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL7A1 | ENST00000681320.1 | c.409C>T | p.Arg137Ter | stop_gained | 4/119 | NM_000094.4 | P1 | ||
COL7A1 | ENST00000328333.12 | c.409C>T | p.Arg137Ter | stop_gained | 3/118 | 1 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461870Hom.: 0 Cov.: 35 AF XY: 0.00000550 AC XY: 4AN XY: 727230
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 19, 2023 | This sequence change creates a premature translational stop signal (p.Arg137*) 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 individual(s) with autosomal recessive dystrophic epidermolysis bullosa (PMID: 16189623). ClinVar contains an entry for this variant (Variation ID: 449472). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 17, 2017 | The R137X nonsense variant in the COL7A1 gene has been reported previously, in the compound heterozygous state with another COL7A1 nonsense variant, in a male infant with Hallopeau-Siemens autosomal recessive dystrophic epidermolysis bullosa (HS-RDEB) and absent collagen VII expression (Sawamura et al., 2005). The R137X variant was also reported in trans with a missense variant in a male patient with RDEB and milder clinical features (Yoshihara et al., 2014). This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R137X is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. However, a therapeutic study of aminoglycoside treatment on cells transfected with R137X improved readthrough and resulted in some synthesis and secretion of a stable full-length collagen VII protein (Cogan et al., 2014). We interpret R137X as a pathogenic variant. - |
Recessive dystrophic epidermolysis bullosa;C0268371:Dominant dystrophic epidermolysis bullosa with absence of skin;C0432321:Pretibial dystrophic epidermolysis bullosa;C0432322:Generalized dominant dystrophic epidermolysis bullosa;C1275114:Epidermolysis bullosa pruriginosa;C1843761:Nonsyndromic congenital nail disorder 8;C1851573:Transient bullous dermolysis of the newborn Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Epidermolysis bullosa dystrophica Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jun 28, 2021 | - - |
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 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at