Submissions for variant NM_000515.5(GH1):c.7A>C (p.Thr3Pro)

dbSNP: rs2001345

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000521816	SCV000621181	uncertain significance	not provided	2018-10-23	criteria provided, single submitter	clinical testing	The T3P variant in the GH1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant is observed in 10/23,584 alleles (0.042%) from individuals of African background and 10/34,282 alleles (0.029%) from individuals of Latino background, with one homozygous control individual reported, in the gnomAD dataset (Lek et al., 2016). The T3P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved across species, and in silico analysis predicts this variant likely does not alter the protein structure/function. We interpret T3P as a variant of uncertain significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488653	SCV004241600	likely benign	not specified	2023-12-22	criteria provided, single submitter	clinical testing	Variant summary: GH1 c.7A>C (p.Thr3Pro) 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 0.00023 in 249884 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in GH1 causing Idiopathic Growth Hormone Deficiency phenotype (6.3e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.7A>C in individuals affected with Idiopathic Growth Hormone Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. The following publications have been ascertained in the context of this evaluation (PMID: 17223997, 18950677). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.