ClinVar Miner

Submissions for variant NM_000079.4(CHRNA1):c.2T>C (p.Met1Thr)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV001136251 SCV001296080 uncertain significance Lethal multiple pterygium syndrome 2018-04-06 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory 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, this variant 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 (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Clinical Services Laboratory,Illumina RCV001136252 SCV001296081 uncertain significance Congenital myasthenic syndrome 2018-04-06 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory 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, this variant 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 (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001136251 SCV001362282 likely pathogenic Lethal multiple pterygium syndrome 2020-12-18 criteria provided, single submitter clinical testing Variant summary: CHRNA1 c.2T>C (p.Met1Thr) alters the initiation codon (the next potential start site is located in exon 5) 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. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 247776 control chromosomes (gnomAD). To our knowledge, no occurrence of c.2T>C in individuals affected with Lethal multiple pterygium syndrome and no experimental evidence demonstrating its impact on protein function have been reported in the literature. A whole-exome sequence (WES) analysis performed at our laboratory identified the variant as a homozygote in one affected fetus with features resembling lethal multiple pterygium syndrome. The same genotype was subsequently identified in two other affected fetuses from the same family. Both parents were identified as obligate carriers and one unaffected sibling tested negative for the variant. This co-segregation with disease in one family suggests that the variant is likely to be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV001136251 SCV001540422 uncertain significance Lethal multiple pterygium syndrome 2020-08-28 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 (rs779169597, ExAC 0.005%). This variant has not been reported in the literature in individuals with CHRNA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 894737). 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.

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