Submissions for variant NM_080669.6(SLC46A1):c.3G>A (p.Met1Ile)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004579636	SCV005062073	likely pathogenic	Congenital defect of folate absorption	2024-03-14	criteria provided, single submitter	clinical testing	Variant summary: SLC46A1 c.3G>A (p.Met1Ile) alters the initiation codon 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, with the next in-frame methionine at codon 75. Two of two in-silico tools predict a benign effect of the variant on protein function. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. To our knowledge, no occurrence of c.3G>A in individuals affected with Congenital Defect Of Folate Absorption has been reported. However, another publications reports an alternate variant affecting the initation codon (c.1A>T, p.M1L) detected in a compound heterozygous individual affected with hereditary folate malabsorption (e.g. Wang_2015). One publication reports experimental evidence evaluating an impact on protein function showing that in vitro expression of the variant results in severely reduced actuivity (Zhao_2011). The following publications have been ascertained in the context of this evaluation (PMID: 21602279, 24534056). No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as likely pathogenic.