ClinVar Miner

Submissions for variant NM_152722.5(HEPACAM):c.614C>T (p.Thr205Ile)

dbSNP: rs746134081
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000503439 SCV000595117 uncertain significance not specified 2016-10-19 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000763712 SCV000894592 uncertain significance Megalencephalic leukoencephalopathy with subcortical cysts 1; Megalencephalic leukoencephalopathy with subcortical cysts 2A; Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without intellectual disability 2018-10-31 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV002524198 SCV003286735 uncertain significance not provided 2022-04-22 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 205 of the HEPACAM protein (p.Thr205Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal recessive HEPACAM-related conditions (PMID: 29915382). ClinVar contains an entry for this variant (Variation ID: 435410). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.
Ambry Genetics RCV002524199 SCV003649611 uncertain significance Inborn genetic diseases 2022-11-10 criteria provided, single submitter clinical testing The c.614C>T (p.T205I) alteration is located in exon 3 (coding exon 3) of the HEPACAM gene. This alteration results from a C to T substitution at nucleotide position 614, causing the threonine (T) at amino acid position 205 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000503439 SCV003934214 uncertain significance not specified 2024-03-11 criteria provided, single submitter clinical testing Variant summary: HEPACAM c.614C>T (p.Thr205Ile) results in a non-conservative amino acid change located in the immunoglobulin subtype 2 domain (IPR003598) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251432 control chromosomes (gnomAD v2.1). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.614C>T has been reported in the literature as a homozygous genotype in an individual with clinical features of Megalencephalic Leukoencephalopathy With Subcortical Cysts 2b such as ataxia and seizures, but brain MRI findings were not reported (Sun_2019). This report does not provide unequivocal conclusions about association of the variant with Megalencephalic Leukoencephalopathy With Subcortical Cysts 2b, Remitting, With Or Without Mental Retardation. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 435410). Based on the evidence outlined above, the variant was classified as uncertain significance.

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