ClinVar Miner

Submissions for variant NM_004304.5(ALK):c.1111G>A (p.Ala371Thr) (rs149968229)

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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 RCV000531158 SCV000429963 benign Neuroblastoma 3 2018-01-13 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Invitae RCV000531158 SCV000648595 benign Neuroblastoma 3 2019-12-26 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000119987 SCV000918415 benign not specified 2018-07-03 criteria provided, single submitter clinical testing Variant summary: ALK c.1111G>A (p.Ala371Thr) results in a non-conservative amino acid change located in the MAM domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 8640-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in ALK causing Neuroblastoma, Susceptibility Type 3 phenotype (4.2e-07), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. The variant, c.1111G>A, has been reported in the literature in an individual diagnosed with Ewing's sarcoma (Zhang_2015). Co-occurrences with other pathogenic variant(s) have been reported (NF2 c.586C>T, p.Arg196X). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "likely benign." Based on the evidence outlined above, the variant was classified as benign.
ITMI RCV000119987 SCV000084117 not provided not specified 2013-09-19 no assertion provided reference population

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