Submissions for variant NM_005199.5(CHRNG):c.753_754del (p.Val253fs)

gnomAD frequency: 0.00026  dbSNP: rs767503038

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000282633	SCV000329801	pathogenic	not provided	2021-04-16	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25957469, 25608830, 30868735, 24038971, 22167768, 34426522, 31589614, 33250842, 32587836, 16826531)
Ambry Genetics	RCV000622703	SCV000741891	pathogenic	Inborn genetic diseases	2016-12-06	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000778602	SCV000914910	pathogenic	CHRNG-Related Disorders	2018-10-26	criteria provided, single submitter	clinical testing	The CHRNG c.753_754delCT (p.Val253AlafsTer44) variant results in a frameshift, and is predicted to result in premature termination of the protein. This variant has been reported in six studies and is found in a total of seven probands including four in a homozygous state and three in a compound heterozygous state (Morgan et al. 2006; Vogt et al. 2012; Robinson et al. 2013; Chong et al. 2015; Kariminejad et al. 2016; Bayram et al. 2016). The variant has been described in probands with both lethal multiple pterygium syndrome and non-lethal (Escobar) phenotypes. Control data are unavailable for this variant, but it is reported at a frequency of 0.00038 in the African population of the Exome Aggregation Consortium. Based on the evidence, the p.Val253AlafsTer44 variant is classified as pathogenic for CHRNG-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000201795	SCV001368372	pathogenic	Autosomal recessive multiple pterygium syndrome	2019-10-28	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1.
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001814005	SCV001755631	pathogenic	Abnormality of prenatal development or birth	2021-07-10	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000282633	SCV001905677	pathogenic	not provided	2021-09-15	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000282633	SCV002019314	pathogenic	not provided	2023-07-18	criteria provided, single submitter	clinical testing
3billion	RCV000020010	SCV002521476	pathogenic	Lethal multiple pterygium syndrome	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.017%). Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000018342). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Fulgent Genetics, Fulgent Genetics	RCV002490395	SCV002799657	pathogenic	Autosomal recessive multiple pterygium syndrome; Lethal multiple pterygium syndrome	2022-01-20	criteria provided, single submitter	clinical testing
Invitae	RCV000282633	SCV003195503	pathogenic	not provided	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Val253Alafs*44) in the CHRNG gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CHRNG are known to be pathogenic (PMID: 16826520). This variant is present in population databases (rs767503038, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with lethal and Escobar variant multiple pterygium syndrome (PMID: 16826531, 22167768, 24038971, 25608830, 27245440). ClinVar contains an entry for this variant (Variation ID: 18342). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000020010	SCV003845110	pathogenic	Lethal multiple pterygium syndrome	2023-02-21	criteria provided, single submitter	clinical testing	Variant summary: CHRNG c.753_754delCT (p.Val253AlafsX44) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00016 in 251490 control chromosomes. c.753_754delCT has been reported in the literature in multiple individuals affected with lethal and Escobar variant multiple pterygium syndrome. These data indicate that the variant is very likely to be associated with disease. 11 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000020010	SCV004171349	pathogenic	Lethal multiple pterygium syndrome		criteria provided, single submitter	clinical testing	The frameshift c.753_754del(p.Val253AlafsTer44) variant in CHRNG gene has been reported previously in homozygous and compound heterozygous states in individual(s) affected with Multiple pterygium syndrome (Chong JX, et. al., 2015; Kariminejad A, et. al., 2016). The p.Val253AlafsTer44 variant has been reported with allele frequency of 0.02% in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). This variant causes a frameshift starting with codon Valine 253, changes this amino acid to Alanine residue, and creates a premature Stop codon at position 44 of the new reading frame, denoted p.Val253AlafsTer44. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000020010	SCV000040308	pathogenic	Lethal multiple pterygium syndrome	2015-04-01	no assertion criteria provided	literature only
OMIM	RCV000201795	SCV000256538	pathogenic	Autosomal recessive multiple pterygium syndrome	2015-04-01	no assertion criteria provided	literature only
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000201795	SCV001167471	pathogenic	Autosomal recessive multiple pterygium syndrome		no assertion criteria provided	research