Submissions for variant NM_014714.4(IFT140):c.3250_3253dup (p.Val1085fs)

dbSNP: rs766084603

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413340	SCV000491452	likely pathogenic	not provided	2016-10-27	criteria provided, single submitter	clinical testing	The c.3250_3253dupGCGG variant in the IFT140 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.3250_3253dupGCGG variant causes a frameshift starting with codon Valine 1085, changes this amino acid to a Glycine residue, and creates a premature Stop codon at position 36 of the new reading frame, denoted p.Val1085GlyfsX36. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.3250_3253dupGCGG variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The c.3250_3253dupGCGG variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Invitae	RCV001386349	SCV001586540	pathogenic	Saldino-Mainzer syndrome	2023-06-15	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 372916). This variant has not been reported in the literature in individuals affected with IFT140-related conditions. This variant is present in population databases (rs766084603, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Val1085Glyfs*36) in the IFT140 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in IFT140 are known to be pathogenic (PMID: 22503633, 23418020, 24009529, 26216056).