Submissions for variant NM_017780.4(CHD7):c.3366G>C (p.Lys1122Asn)

gnomAD frequency: 0.00005  dbSNP: rs41272440

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000416000	SCV000113767	uncertain significance	not provided	2016-10-10	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000346766	SCV000474431	uncertain significance	Hypogonadotropic hypogonadism 5 with or without anosmia	2018-01-13	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.
CeGaT Center for Human Genetics Tuebingen	RCV000416000	SCV000493442	uncertain significance	not provided	2023-07-01	criteria provided, single submitter	clinical testing	CHD7: PP3
Invitae	RCV001362262	SCV001558270	uncertain significance	CHARGE association	2023-10-11	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 1122 of the CHD7 protein (p.Lys1122Asn). This variant is present in population databases (rs41272440, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with CHD7-related conditions. ClinVar contains an entry for this variant (Variation ID: 95786). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CHD7 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.
Ambry Genetics	RCV002453404	SCV002615494	likely benign	Inborn genetic diseases	2022-06-02	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Fulgent Genetics, Fulgent Genetics	RCV002490718	SCV002789903	uncertain significance	CHARGE association; Hypogonadotropic hypogonadism 5 with or without anosmia	2022-05-18	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000416000	SCV003831957	uncertain significance	not provided	2021-05-21	criteria provided, single submitter	clinical testing