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)
ClinVar Genomic variation as it relates to human health
NM_004463.3(FGD1):c.527del (p.Pro176fs)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(8)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic
8
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_004463.3(FGD1):c.527del (p.Pro176fs)
Variation ID: 374329 Accession: VCV000374329.14
- Type and length
-
Deletion, 1 bp
- Location
-
Cytogenetic: Xp11.22 X: 54470715 (GRCh38) [ NCBI UCSC ] X: 54497148 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jan 16, 2017 Nov 17, 2024 Apr 4, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_004463.3:c.527del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004454.2:p.Pro176fs frameshift NM_004463.2:c.527delC NC_000023.11:g.54470722del NC_000023.10:g.54497155del NG_008054.1:g.30452del - Protein change
- P176fs
- Other names
- -
- Canonical SPDI
- NC_000023.11:54470714:GGGGGGGG:GGGGGGG
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| FGD1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
338 | 542 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Apr 4, 2024 | RCV000415303.7 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 9, 2017 | RCV000624698.3 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Dec 5, 2022 | RCV002272226.5 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Apr 27, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Aarskog syndrome
Affected status: yes
Allele origin:
germline
|
Centogene AG - the Rare Disease Company
Accession: SCV002059546.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
|
|
|
Pathogenic
(Jul 26, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002558425.2
First in ClinVar: Aug 08, 2022 Last updated: Mar 04, 2023 |
Comment:
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 … (more)
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) (less)
|
|
|
Pathogenic
(Dec 05, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003444663.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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). (less)
|
|
|
Pathogenic
(Apr 04, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Aarskog syndrome
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004809360.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
|
|
|
Pathogenic
(Mar 09, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000741314.4
First in ClinVar: Apr 15, 2018 Last updated: May 01, 2024 |
Comment:
The c.527delC pathogenic mutation, located in coding exon 3 of the FGD1 gene, results from a deletion of one nucleotide at nucleotide position 527, causing … (more)
The c.527delC pathogenic mutation, located in coding exon 3 of the FGD1 gene, results from a deletion of one nucleotide at nucleotide position 527, causing a translational frameshift with a predicted alternate stop codon (p.P176Hfs*39). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
|
|
|
Pathogenic
(May 12, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Aarskog syndrome
(X-linked recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002767694.2
First in ClinVar: Dec 24, 2022 Last updated: Jul 23, 2024 |
Comment:
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 … (more)
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 (less)
|
|
|
Pathogenic
(Aug 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Aarskog syndrome
(X-linked recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center
Accession: SCV005397392.1
First in ClinVar: Nov 17, 2024 Last updated: Nov 17, 2024 |
Comment:
This sequence variant is a single nucleotide deletion in exon 3 of 18 of the FGD1 gene that results in an early termition codon 39 … (more)
This sequence variant is a single nucleotide deletion in exon 3 of 18 of the FGD1 gene that results in an early termition codon 39 amino acids downstream of the frameshift at codon 176. This variant is predicted to generate a non-functiol allele through either the expression of a truncated protein or a loss of FGD1 expression due to nonsense mediated decay. This is a previously reported variant (ClinVar 374329) that has been observed in the literature in an individual with phenotypes consistent with Aarskog-Scott syndrome (PMID: 27959697). This variant is absent from the gnomAD population database (0/~131000 alleles). Haploinsufficiency in FGD1 is a known mechanism of disease. Based upon the evidence, we consider this variant to be pathogenic. ACMG Criteria: PM2, PVS1 (less)
|
|
|
Pathogenic
(Dec 19, 2014)
|
no assertion criteria provided
Method: clinical testing
|
Aarskog syndrome
(X-linked inheritance)
Affected status: yes
Allele origin:
de novo
|
Baylor Genetics
Accession: SCV000328808.1
First in ClinVar: Jan 16, 2017 Last updated: Jan 16, 2017 |
Comment:
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 … (more)
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]. (less)
Number of individuals with the variant: 1
Age: 0-9 years
Sex: male
Ethnicity/Population group: Hispanic Americans
|
Comment:
Comment:
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).
Comment:
The c.527delC pathogenic mutation, located in coding exon 3 of the FGD1 gene, results from a deletion of one nucleotide at nucleotide position 527, causing a translational frameshift with a predicted alternate stop codon (p.P176Hfs*39). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Comment:
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
Comment:
This sequence variant is a single nucleotide deletion in exon 3 of 18 of the FGD1 gene that results in an early termition codon 39 amino acids downstream of the frameshift at codon 176. This variant is predicted to generate a non-functiol allele through either the expression of a truncated protein or a loss of FGD1 expression due to nonsense mediated decay. This is a previously reported variant (ClinVar 374329) that has been observed in the literature in an individual with phenotypes consistent with Aarskog-Scott syndrome (PMID: 27959697). This variant is absent from the gnomAD population database (0/~131000 alleles). Haploinsufficiency in FGD1 is a known mechanism of disease. Based upon the evidence, we consider this variant to be pathogenic. ACMG Criteria: PM2, PVS1
Comment:
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].
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
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)
Comment:
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).
Comment:
The c.527delC pathogenic mutation, located in coding exon 3 of the FGD1 gene, results from a deletion of one nucleotide at nucleotide position 527, causing a translational frameshift with a predicted alternate stop codon (p.P176Hfs*39). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Comment:
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
Comment:
This sequence variant is a single nucleotide deletion in exon 3 of 18 of the FGD1 gene that results in an early termition codon 39 amino acids downstream of the frameshift at codon 176. This variant is predicted to generate a non-functiol allele through either the expression of a truncated protein or a loss of FGD1 expression due to nonsense mediated decay. This is a previously reported variant (ClinVar 374329) that has been observed in the literature in an individual with phenotypes consistent with Aarskog-Scott syndrome (PMID: 27959697). This variant is absent from the gnomAD population database (0/~131000 alleles). Haploinsufficiency in FGD1 is a known mechanism of disease. Based upon the evidence, we consider this variant to be pathogenic. ACMG Criteria: PM2, PVS1
Comment:
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].
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Resolution of Disease Phenotypes Resulting from Multilocus Genomic Variation. | Posey JE | The New England journal of medicine | 2017 | PMID: 27959697 |
| Identification of novel mutations in Mexican patients with Aarskog-Scott syndrome. | Pérez-Coria M | Molecular genetics & genomic medicine | 2015 | PMID: 26029706 |
| CHIPS for genetic testing to improve a regional clinical genetic service. | Niida Y | Clinical genetics | 2015 | PMID: 25046119 |
| Novel FGD1 mutation underlying Aarskog-Scott syndrome with myopathy and distal arthropathy. | Al-Semari A | Clinical dysmorphology | 2013 | PMID: 23211637 |
| Fraternal twins with Aarskog-Scott syndrome due to maternal germline mosaicism. | Pilozzi-Edmonds L | American journal of medical genetics. Part A | 2011 | PMID: 21739585 |
| Aarskog-Scott syndrome: clinical update and report of nine novel mutations of the FGD1 gene. | Orrico A | American journal of medical genetics. Part A | 2010 | PMID: 20082460 |
Text-mined citations for rs756586058 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 19, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.