ClinVar Miner

Submissions for variant NM_005334.3(HCFC1):c.1429G>A (p.Ala477Thr)

gnomAD frequency: 0.00002  dbSNP: rs782010359
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000224972 SCV000281772 uncertain significance Methylmalonic acidemia with homocystinuria, type cblX 2016-03-17 criteria provided, single submitter research
GeneDx RCV000493756 SCV000583278 uncertain significance not provided 2020-02-11 criteria provided, single submitter clinical testing Reported hemizygous in individuals with intellectual disability and seizures (Jolly et al., 2015; Bowling et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25740848, 28554332)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000224972 SCV002768467 uncertain significance Methylmalonic acidemia with homocystinuria, type cblX 2020-10-19 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as 3B-VUS. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with HCFC1-related intellectual disability. (I) 0109 - This gene is associated with X-linked recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to threonine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (1 heterozygote, 0 homozygotes, 1 hemizygote). (SP) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported as a variant of unknown significance in individuals with intellectual disability (ClinVar, PMID: 25740848, 28554332). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Ambry Genetics RCV002516244 SCV003570206 likely benign Inborn genetic diseases 2022-08-23 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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