rs768415785
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_198129.4(LAMA3):c.7828C>T(p.Arg2610Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,694 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). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_198129.4 stop_gained
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LAMA3 | NM_198129.4 | c.7828C>T | p.Arg2610Ter | stop_gained | 60/75 | ENST00000313654.14 | |
LAMA3 | NM_000227.6 | c.3001C>T | p.Arg1001Ter | stop_gained | 23/38 | ENST00000269217.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LAMA3 | ENST00000313654.14 | c.7828C>T | p.Arg2610Ter | stop_gained | 60/75 | 1 | NM_198129.4 | P1 | |
LAMA3 | ENST00000269217.11 | c.3001C>T | p.Arg1001Ter | stop_gained | 23/38 | 1 | NM_000227.6 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251394Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135862
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461694Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9AN XY: 727150
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Junctional epidermolysis bullosa gravis of Herlitz Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Dec 01, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 04, 2019 | Variant summary: LAMA3 c.3001C>T (p.Arg1001X) 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. At-least one splice variant downstream of this position has been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251394 control chromosomes. c.3001C>T has been reported in the literature in compound heterozygosity with another truncating alteration in at-least one individual affected with Herlitz Junctional Epidermolysis Bullosa (hemidesmosomal variants of EB (HEB), Varki_2006). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic, and another classified the variant as uncertain significance. Based on the well established etiology of loss of function variants in the pathophysiology of JEB and the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 19, 2023 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 555355). This premature translational stop signal has been observed in individual(s) with autosomal recessive epidermolysis bullosa (PMID: 16473856, 33274474). This variant is present in population databases (rs768415785, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Arg1001*) in the LAMA3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LAMA3 are known to be pathogenic (PMID: 10366601, 11810295, 12915477, 16473856, 17362460, 22434185, 23869449, 27827380, 28087116). - |
LAMA3-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Oct 10, 2018 | This variant is a stop-gained variant, which was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018) and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score for this variant, it could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. Due to the potential impact of stop-gained variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for this disease. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at