Submissions for variant NM_004473.4(FOXE1):c.743C>G (p.Ala248Gly)

gnomAD frequency: 0.00247  dbSNP: rs538912281

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mendelics	RCV000988238	SCV001137879	likely benign	Bamforth-Lazarus syndrome	2024-04-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317142	SCV004020979	uncertain significance	not specified	2023-06-27	criteria provided, single submitter	clinical testing	Variant summary: FOXE1 c.743C>G (p.Ala248Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0028 in 150478 control chromosomes, predominantly at a frequency of 0.005 within the Non-Finnish European subpopulation in the gnomAD database (v3.1 genomes dataset), including 2 homozygotes. The available data on variant occurrences in the general population are insufficient to allow clear conclusions about variant significance, however, the large number of heterozygotes (i.e. 425 carriers) are not suggestive of a highly penetrant variant associated with, early-onset, autosomal dominant disease. The variant, c.743C>G has been reported in the literature in heterozygous state to segregate with non-medullary thyroid carcinoma (NMTC) in a family, and was also identified in a sporadic case of NMTC, although no other loci associated with NMTC were assessed (Pereira_2015). The variant has also been reported heterozygous state in other individuals affected with primary congenital hypothyroidism (e.g., Choukair_2020, deFilippis_2017), however without strong evidence for causality (e.g., co-occurrence with other potentially causative variants and lack of co-segregation data). These reports therefore do not allow conclusions about association of the variant with disease. At least one publication reported experimental evidence evaluating an impact on protein function, finding that the variant results in significantly increased cell proliferation and migration, and resulted in significantly increased WNT5A expression in vitro (Pereira_2015). The following publications have been ascertained in the context of this evaluation (PMID: 32428920, 25381600, 28444304). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as pathogenic, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Revvity Omics, Revvity	RCV000988238	SCV004234837	uncertain significance	Bamforth-Lazarus syndrome	2019-07-23	criteria provided, single submitter	clinical testing
OMIM	RCV000190467	SCV000245350	pathogenic	Thyroid cancer, nonmedullary, 4	2015-05-01	no assertion criteria provided	literature only