Submissions for variant NM_052989.3(IFT122):c.565C>T (p.Arg189Ter)

gnomAD frequency: 0.00009  dbSNP: rs138329739

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000705716	SCV000834729	pathogenic	Cranioectodermal dysplasia 1	2022-07-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg240*) in the IFT122 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in IFT122 are known to be pathogenic (PMID: 20493458, 23826986, 26792575). This variant is present in population databases (rs138329739, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with IFT122-related conditions. ClinVar contains an entry for this variant (Variation ID: 581786). For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina	RCV000705716	SCV000915014	uncertain significance	Cranioectodermal dysplasia 1	2017-08-29	criteria provided, single submitter	clinical testing	The IFT122 c.718C>T (p.Arg240Ter) variant is a stop-gained variant, which was observed by ICSL 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 for this variant, it 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. No publications were found based on this search. Due to the potential impact of stop-gained variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for cranioectodermal dysplasia.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000705716	SCV004100290	pathogenic	Cranioectodermal dysplasia 1	2023-09-29	criteria provided, single submitter	clinical testing	Variant summary: IFT122 c.718C>T (p.Arg240X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, a commonly known mechanism for disease. The variant allele was found at a frequency of 5.2e-05 in 251482 control chromosomes (gnomAD). To our knowledge, no occurrence of c.718C>T in individuals affected with Cranioectodermal Dysplasia 1 and no experimental evidence demonstrating its impact on protein function have been reported. 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 pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003392543	SCV004119053	likely pathogenic	IFT122-related disorder	2024-07-28	no assertion criteria provided	clinical testing	The IFT122 c.718C>T variant is predicted to result in premature protein termination (p.Arg240*). This variant has not been reported in an individual with IFT122 related disease. This variant is reported in 0.028% of alleles in individuals of African descent in gnomAD. Nonsense variants in IFT122 are expected to be pathogenic. This variant is interpreted as likely pathogenic.