Submissions for variant NM_014425.5(INVS):c.1727G>A (p.Arg576Gln)

gnomAD frequency: 0.00003  dbSNP: rs758506682

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000729273	SCV000856920	uncertain significance	not provided	2017-09-13	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001212274	SCV001383854	uncertain significance	Nephronophthisis	2022-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 576 of the INVS protein (p.Arg576Gln). This variant is present in population databases (rs758506682, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with INVS-related conditions. ClinVar contains an entry for this variant (Variation ID: 594062). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine 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.
GeneDx	RCV000729273	SCV002762527	uncertain significance	not provided	2022-06-10	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Fulgent Genetics, Fulgent Genetics	RCV002493312	SCV002789436	uncertain significance	Infantile nephronophthisis	2021-09-09	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003303209	SCV003990255	uncertain significance	Inborn genetic diseases	2023-05-24	criteria provided, single submitter	clinical testing	The c.1727G>A (p.R576Q) alteration is located in exon 12 (coding exon 11) of the INVS gene. This alteration results from a G to A substitution at nucleotide position 1727, causing the arginine (R) at amino acid position 576 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004689869	SCV005185807	uncertain significance	not specified	2024-05-15	criteria provided, single submitter	clinical testing	Variant summary: INVS c.1727G>A (p.Arg576Gln) results in a 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 4.8e-05 in 251456 control chromosomes. To our knowledge, no occurrence of c.1727G>A in individuals affected with Infantile Nephronophthisis and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 594062). Based on the evidence outlined above, the variant was classified as uncertain significance.