Submissions for variant NM_004463.3(FGD1):c.527del (p.Pro176fs)

dbSNP: rs756586058

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000624698	SCV000741314	pathogenic	Inborn genetic diseases	2016-04-05	criteria provided, single submitter	clinical testing
Centogene AG - the Rare Disease Company	RCV000415303	SCV002059546	pathogenic	Aarskog syndrome	2020-04-27	criteria provided, single submitter	clinical testing
GeneDx	RCV002272226	SCV002558425	pathogenic	not provided	2022-07-26	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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27959697, 34189097)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000415303	SCV002767694	pathogenic	Aarskog syndrome	2020-05-12	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0109 - This gene is known to be associated with X-linked recessive disease. (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (exon 3 of 18 ) . (P) 0253 - Variant is hemizygous. (N) 0301 - Variant is absent from gnomAD. (P) 0701 - Comparable variants have very strong previous evidence for pathogenicity (ClinVar, Orrico, A. et al. (2010)). (P) 0803 - Low previous evidence of pathogenicity in unrelated individuals (ClinVar). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1102 - Strong phenotype match. (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Invitae	RCV002272226	SCV003444663	pathogenic	not provided	2022-12-05	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: 374329). This premature translational stop signal has been observed in individual(s) with FGD1-related conditions (PMID: 27959697). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Pro176Hisfs*39) in the FGD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FGD1 are known to be pathogenic (PMID: 21739585, 23211637, 25046119, 26029706).
Baylor Genetics	RCV000415303	SCV000328808	pathogenic	Aarskog syndrome	2014-12-19	no assertion criteria provided	clinical testing	Our laboratory reported dual molecular diagnoses in PAFAH1B1 (NM_000430.3, c.484G>A) and FGD1 (NM_004463.2, c.527delC) in this individual with reported features of intrauterine growth restriction, delayed motor milestones, delayed speech, autism, intellectual disability, hearing loss, hypotonia, seizure disorder, ataxia, dysmorphic features, short stature, microcephaly, failure to thrive, eye anomalies, skeletal abnormalities and scoliosis, and structural brain anomalies. The PAFAH1B1 variant has been reported in one patient with a mild LIS1 phenotype [PMID: 11115846, 12885786]. The FGD1 variant is predicted to cause a frameshift and is categorized as deleterious by ACMGG guidelines [PMID: 18414213].