Submissions for variant NM_004463.3(FGD1):c.527dup (p.Leu177fs)

dbSNP: rs756586058

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000790801	SCV000229043	pathogenic	not provided	2014-06-05	criteria provided, single submitter	clinical testing
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000177205	SCV000583576	likely pathogenic	Aarskog syndrome	2017-06-01	criteria provided, single submitter	research
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000177205	SCV000781476	pathogenic	Aarskog syndrome	2016-11-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000790801	SCV001788262	pathogenic	not provided	2022-09-13	criteria provided, single submitter	clinical testing	Reported in multiple individuals with clinical features of Aarskog-Scott syndrome from two unrelated families (Orrico et al., 2004); 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 in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 14560308)
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000790801	SCV002051714	pathogenic	not provided	2021-01-26	criteria provided, single submitter	clinical testing	PVS1, PM2, PS4_Moderate
3billion	RCV000177205	SCV002058304	pathogenic	Aarskog syndrome	2022-01-03	criteria provided, single submitter	clinical testing	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 (PVS1_VS). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000196389, PMID:14560308). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002315, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Invitae	RCV000790801	SCV003255784	pathogenic	not provided	2022-12-15	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: 196389). This premature translational stop signal has been observed in individual(s) with FGD1-related conditions (PMID: 14560308, 29276006). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Leu177Thrfs*40) 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).
PreventionGenetics, part of Exact Sciences	RCV003407654	SCV004115344	pathogenic	FGD1-related condition	2023-07-26	criteria provided, single submitter	clinical testing	The FGD1 c.527dupC variant is predicted to result in a frameshift and premature protein termination (p.Leu177Thrfs*40). This variant was reported in multiple individuals with Aarskog-Scott syndrome (referred to as 528insC in Orrico et al. 2004. PubMed ID: 14560308; White et al. 2017. PubMed ID: 29276006). This variant is reported in 1.5% of alleles in individuals of European (Finnish) descent in gnomAD; however, this variant is located in a region of poor sequence quality making population frequency estimates unreliable (http://gnomad.broadinstitute.org/variant/X-54497147-T-TG). Frameshift variants in FGD1 are expected to be pathogenic. This variant is interpreted as pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000177205	SCV004800976	pathogenic	Aarskog syndrome	2024-03-13	criteria provided, single submitter	curation	The hemizygous p.Leu177ThrfsTer40 variant in FGD1 was identified by our study in one individual with short stature and congenital fibrosis of the extraocular muscles, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Engle lab (https://kirbyneuro.org/EngleLab/). The p.Leu177ThrfsTer40 variant in FGD1 has been previously reported in 4 unrelated individuals with Aarskog-Scott syndrome (PMID: 14560308, PMID: 29276006, PMID: 35388608, ClinVar Accession SCV002058304.1) and segregated with disease in 3 affected male relatives from one family, 2 of whom were monozygotic twins (PMID: 14560308). The number of reported affected individuals with this variant is slightly greater than expected compared to non-affected individuals with this variant. Data from large population studies is insufficient to assess the frequency of this variant. This variant has also been reported in ClinVar (Variation ID: 196389) and has been interpreted as pathogenic or likely pathogenic by multiple submitters. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 177 and leads to a premature termination codon 40 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the FGD1 gene is an established disease mechanism in X-linked recessive Aarskog-Scott syndrome. In summary, this variant meets criteria to be classified as pathogenic for X-linked recessive Aarskog-Scott syndrome. ACMG/AMP Criteria applied: PVS1, PS4_Moderate, PP1 (Richards 2015).
OMIM	RCV000177205	SCV000031808	pathogenic	Aarskog syndrome	2004-01-01	no assertion criteria provided	literature only