NM_004463.3(FGD1):c.1829G>A (p.Arg610Gln) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jun 14, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000309625.4

Allele description [Variation Report for NM_004463.3(FGD1):c.1829G>A (p.Arg610Gln)]

NM_004463.3(FGD1):c.1829G>A (p.Arg610Gln)

Gene:

FGD1:FYVE, RhoGEF and PH domain containing 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xp11.22

Genomic location:

Preferred name:

NM_004463.3(FGD1):c.1829G>A (p.Arg610Gln)

HGVS:

NC_000023.11:g.54456233C>T
NG_008054.1:g.44934G>A
NM_004463.3:c.1829G>AMANE SELECT
NP_004454.2:p.Arg610Gln
NC_000023.10:g.54482666C>T
NM_004463.2:c.1829G>A
P98174:p.Arg610Gln

Protein change:

R610Q; ARG610GLN

Links:

UniProtKB: P98174#VAR_015237; OMIM: 300546.0002; dbSNP: rs28935497

NCBI 1000 Genomes Browser:

rs28935497

Molecular consequence:

NM_004463.3:c.1829G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000329747	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Pathogenic (Mar 30, 2016)	germline	clinical testing	Citation Link,
SCV003445242	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 14, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 10930571, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000329747

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Pathogenic
(Mar 30, 2016)

germline

clinical testing

Citation Link,

SCV003445242

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jun 14, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A mutation in the pleckstrin homology (PH) domain of the FGD1 gene in an Italian family with faciogenital dysplasia (Aarskog-Scott syndrome).

Orrico A, Galli L, Falciani M, Bracci M, Cavaliere ML, Rinaldi MM, Musacchio A, Sorrentino V.

FEBS Lett. 2000 Aug 4;478(3):216-20.

PubMed [citation]

PMID:: 10930571

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From GeneDx, SCV000329747.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The R610Q pathogenic variant in the FGD1 gene has been reported previously in association with Aarskog-Scott syndrome (Orrico et al., 2000). Functional studies demonstrate that the R610Q variant results in aberrant FGD1 activity (Zou et al., 2011). This variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R610Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R610Q as a pathogenic variant.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003445242.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

ClinVar contains an entry for this variant (Variation ID: 10825). This missense change has been observed in individuals with Aarskog-Scott syndrome (PMID: 10930571; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 610 of the FGD1 protein (p.Arg610Gln). For these reasons, this variant has been classified as Pathogenic. 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) performed at Invitae indicates that this missense variant is expected to disrupt FGD1 protein function.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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