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

gnomAD frequency: 0.00001  dbSNP: rs779169597

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, 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 Laboratory Services, 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	2023-07-28	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. Additionally, pathogenic variants have been reported upstream of the next in-frame methionine. 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. Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014: one submitter has classified the variant as likely pathogenic while two classified as VUS. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae	RCV001136251	SCV001540422	uncertain significance	Lethal multiple pterygium syndrome	2023-07-31	criteria provided, single submitter	clinical testing	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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 894737). This variant has not been reported in the literature in individuals affected with CHRNA1-related conditions. This variant is present in population databases (rs779169597, gnomAD 0.08%). This sequence change affects the initiator methionine of the CHRNA1 mRNA. The next in-frame methionine is located at codon 164.
GeneDx	RCV001564791	SCV001788008	likely pathogenic	not provided	2020-11-19	criteria provided, single submitter	clinical testing	Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge