Submissions for variant NM_000369.5(TSHR):c.823G>A (p.Ala275Thr)

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	RCV004689531	SCV005185787	likely pathogenic	Hypothyroidism due to TSH receptor mutations	2024-05-30	criteria provided, single submitter	clinical testing	Variant summary: TSHR c.823G>A (p.Ala275Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251482 control chromosomes. c.823G>A has been reported in the literature in heterozygous and compound heterozygous state in individuals affected with congenital hypothyroidsm (e.g. Long_2021, Wang_2020, Sun_2018). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal Gq-11 signaling activity in 293T cells (Fang_2019). The following publications have been ascertained in the context of this evaluation (PMID: 31356790, 34539567, 29650690, 32425884). 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.