ClinVar Miner

Submissions for variant NM_024306.5(FA2H):c.337C>T (p.Arg113Trp)

gnomAD frequency: 0.00053  dbSNP: rs141276237
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001712218 SCV000520824 likely benign not provided 2020-11-23 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 24299421)
Invitae RCV000633072 SCV000754284 likely benign Spastic paraplegia 2021-12-12 criteria provided, single submitter clinical testing
Illumina Laboratory Services,Illumina RCV001115914 SCV001273930 uncertain significance Hereditary spastic paraplegia 35 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Baylor Genetics RCV001115914 SCV001529393 uncertain significance Hereditary spastic paraplegia 35 2018-03-02 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Genetic Services Laboratory,University of Chicago RCV001821170 SCV002066701 uncertain significance not specified 2017-07-20 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,The Hospital for Sick Children RCV001848762 SCV002104678 uncertain significance Hereditary spastic paraplegia 2018-02-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001821170 SCV002547565 likely benign not specified 2022-05-26 criteria provided, single submitter clinical testing Variant summary: FA2H c.337C>T (p.Arg113Trp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0007 in 251494 control chromosomes (gnomAD), predominantly at a frequency of 0.00098 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 5 fold of the estimated maximal expected allele frequency for a pathogenic variant in FA2H causing Neurodegeneration With Brain Iron Accumulation phenotype (0.00019), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. To our knowledge, no occurrence of c.337C>T in individuals affected with Neurodegeneration With Brain Iron Accumulation and no experimental evidence demonstrating its impact on protein function have been reported. Six ClinVar submitters have assessed the variant since 2014: four classified the variant as of uncertain significance and two as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.

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