Submissions for variant NM_000174.5(GP9):c.236C>T (p.Thr79Ile)

gnomAD frequency: 0.00046  dbSNP: rs200640594

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001145150	SCV001305792	uncertain significance	Bernard Soulier syndrome	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002559401	SCV003289794	uncertain significance	not provided	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 79 of the GP9 protein (p.Thr79Ile). This variant is present in population databases (rs200640594, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with GP9-related conditions. ClinVar contains an entry for this variant (Variation ID: 900152). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
PreventionGenetics, part of Exact Sciences	RCV003405353	SCV004106471	uncertain significance	GP9-related disorder	2023-08-01	criteria provided, single submitter	clinical testing	The GP9 c.236C>T variant is predicted to result in the amino acid substitution p.Thr79Ile. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.12% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-128780818-C-T). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004702650	SCV005204608	uncertain significance	not specified	2024-06-19	criteria provided, single submitter	clinical testing	Variant summary: GP9 c.236C>T (p.Thr79Ile) results in a non-conservative amino acid change located in the Leucine-rich repeat N-terminal domain (IPR000372) of 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 0.00026 in 248086 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in GP9 causing Bernard Soulier Syndrome (0.00026 vs 0.00074), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.236C>T in individuals affected with Bernard Soulier Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 900152). Based on the evidence outlined above, the variant was classified as uncertain significance.