Submissions for variant NM_000369.5(TSHR):c.1957C>G (p.Leu653Val)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003557833	SCV004297144	pathogenic	not provided	2023-02-16	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 653 of the TSHR protein (p.Leu653Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal recessive TSHR-related conditions (PMID: 17456567, 19240155). It has also been observed to segregate with disease in related individuals. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TSHR protein function. Experimental studies have shown that this missense change affects TSHR function (PMID: 17456567). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004783080	SCV005395847	pathogenic	Hypothyroidism due to TSH receptor mutations	2024-09-16	criteria provided, single submitter	clinical testing	Variant summary: TSHR c.1957C>G (p.Leu653Val) results in a conservative amino acid change located in the GPCR, rhodopsin-like, 7TM domain (IPR017452) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251486 control chromosomes. c.1957C>G has been reported in the literature in multiple homozygous individuals in a consanguineous family affected with Hypothyroidism Due To TSH Receptor Mutations (Grasberger_2007). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in more than 80% reduction in TSH-induced inositol phosphates and significantly higher concentration of TSH required to elicit cAMP-IP signaling cascades in an in vitro cellular assay (Grasberger_2007). The following publications have been ascertained in the context of this evaluation (PMID: 17456567, 19240155, 25557138). ClinVar contains an entry for this variant (Variation ID: 2736138). Based on the evidence outlined above, the variant was classified as pathogenic.