Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV002266219 | SCV002547812 | likely pathogenic | Lethal multiple pterygium syndrome | 2022-05-09 | criteria provided, single submitter | clinical testing | Variant summary: CHRNA1 c.1A>G (p.Met1?, aka p.Met1Val) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.3e-05 (i.e.in 5 heterozygous carriers) in 150962 control chromosomes (gnomAD v3.1, genomes dataset). The presence of the variant in healthy heterozygous individuals suggests that the variant is likely not associated with disease in a dominant manner. To our knowledge, no occurrence of c.1A>G in individuals affected with Lethal Multiple Pterygium Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. On the other hand, a whole-exome sequencing (WES) analysis performed at our laboratory identified another start-loss variant (c.2T>C) in homozygous state in three affected fetuses with features resembling lethal multiple pterygium syndrome from the same family, while both parents were identified as obligate carriers and one unaffected sibling tested negative for the variant. Co-segregation with disease in one family for a similar start-loss variant suggests that the variant is likely to be associated with disease. |
| Invitae | RCV002266219 | SCV004369397 | uncertain significance | Lethal multiple pterygium syndrome | 2023-02-21 | criteria provided, single submitter | clinical testing | This sequence change affects the initiator methionine of the CHRNA1 mRNA. The next in-frame methionine is located at codon 164. This variant is present in population databases (rs146464862, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with CHRNA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1696075). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |