Variant summary: FAM161A c.1567C>T (p.Arg523X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4.8e-05 in 249446 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in FAM161A causing Retinitis Pigmentosa (4.8e-05 vs 0.00063), allowing no conclusion about variant significance. c.1567C>T has been reported in the literature in multiple individuals affected with Retinitis Pigmentosa. These data indicate that the variant is very likely to be associated with disease. Eight 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.
ClinVar Genomic variation as it relates to human health
NM_001201543.2(FAM161A):c.1567C>T (p.Arg523Ter)
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.
(16)
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
16
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001201543.2(FAM161A):c.1567C>T (p.Arg523Ter)
Variation ID: 38 Accession: VCV000000038.36
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2p15 2: 61839437 (GRCh38) [ NCBI UCSC ] 2: 62066572 (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 Apr 4, 2013 Oct 20, 2024 Mar 12, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001201543.2:c.1567C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001188472.1:p.Arg523Ter nonsense NM_032180.3:c.1567C>T NP_115556.2:p.Arg523Ter nonsense NR_037710.2:n.1530C>T non-coding transcript variant NC_000002.12:g.61839437G>A NC_000002.11:g.62066572G>A NG_028125.1:g.19707C>T - Protein change
- R523*
- Other names
- -
- Canonical SPDI
- NC_000002.12:61839436:G:A
-
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.
-
0.00020 (A)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00002
1000 Genomes Project 0.00020
1000 Genomes Project 30x 0.00031
- 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. |
|||
| FAM161A | - | - |
GRCh38 GRCh37 |
781 | 874 | |
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 (4) |
criteria provided, multiple submitters, no conflicts
|
Mar 12, 2024 | RCV000000055.10 | |
| Pathogenic (2) |
criteria provided, single submitter
|
Mar 15, 2019 | RCV000787606.3 | |
| Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
|
Mar 7, 2024 | RCV000790648.26 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Apr 27, 2022 | RCV001003031.6 |
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
(Aug 15, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000229236.5
First in ClinVar: Jun 28, 2015 Last updated: Jul 30, 2019 |
Number of individuals with the variant: 2
Sex: mixed
|
|
|
Pathogenic
(Mar 15, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Retinal dystrophy
Affected status: yes
Allele origin:
germline
|
Blueprint Genetics
Accession: SCV001239774.1
First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020
Comment:
My Retina Tracker patient
|
|
|
|
Pathogenic
(Apr 27, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Retinitis pigmentosa
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002511622.1
First in ClinVar: May 16, 2022 Last updated: May 16, 2022 |
Comment:
Variant summary: FAM161A c.1567C>T (p.Arg523X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: FAM161A c.1567C>T (p.Arg523X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4.8e-05 in 249446 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in FAM161A causing Retinitis Pigmentosa (4.8e-05 vs 0.00063), allowing no conclusion about variant significance. c.1567C>T has been reported in the literature in multiple individuals affected with Retinitis Pigmentosa. These data indicate that the variant is very likely to be associated with disease. Eight 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. (less)
|
|
|
Pathogenic
(Dec 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001586470.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg523*) in the FAM161A gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg523*) in the FAM161A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FAM161A are known to be pathogenic (PMID: 20705278, 20705279, 24651477). 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 premature translational stop signal has been observed in individuals with retinitis pigmentosa (PMID: 20705279, 28945494). ClinVar contains an entry for this variant (Variation ID: 38). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Mar 07, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV005201361.1
First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more)
Nonsense 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: 25525159, 28559085, 31456290, 34426522, 31589614, 28945494, 31345219, 32531858, 32938956, 20705279, 31814694) (less)
|
|
|
Pathogenic
(Sep 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV004042074.11
First in ClinVar: Oct 14, 2023 Last updated: Oct 20, 2024 |
Comment:
FAM161A: PM3:Very Strong, PVS1, PM2
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Apr 01, 2021)
|
criteria provided, single submitter
Method: curation
|
Retinitis pigmentosa
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001950275.1
First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
Comment:
The p.Arg523Ter variant in FAM161A was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics … (more)
The p.Arg523Ter variant in FAM161A was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PVS1, PM2, PM3-P. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. (less)
|
|
|
Pathogenic
(Oct 18, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Retinitis pigmentosa 28
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000487104.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 24, 2022 |
|
|
|
Pathogenic
(Mar 12, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Retinitis pigmentosa 28
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004195925.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Sep 10, 2010)
|
no assertion criteria provided
Method: literature only
|
RETINITIS PIGMENTOSA 28
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000020198.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In affected members from 3 families segregating autosomal recessive retinitis pigmentosa (RP28; 606068), 2 of Syrian Jewish origin and 1 of Libyan Jewish origin, Bandah-Rozenfeld … (more)
In affected members from 3 families segregating autosomal recessive retinitis pigmentosa (RP28; 606068), 2 of Syrian Jewish origin and 1 of Libyan Jewish origin, Bandah-Rozenfeld et al. (2010) identified homozygosity for a 1567C-T transition in exon 3 of the FAM161A gene, resulting in an arg523-to-ter (R523X) substitution. Affected individuals from 3 more RP families, either of North African or European Jewish origin, were compound heterozygous for R523X and a 2-bp deletion in FAM161A (613596.0003). On the basis of haplotype data, the R523X mutation was determined to be a founder mutation in the Israeli Jewish population; the R523X mutation was not detected in 108 North African Jewish controls. (less)
|
|
|
Pathogenic
(Apr 01, 2018)
|
no assertion criteria provided
Method: research
|
Retinal dystrophy
Affected status: yes
Allele origin:
unknown
|
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet
Study: VeluxRD
Accession: SCV000926590.2 First in ClinVar: Jul 21, 2019 Last updated: Sep 03, 2023 |
|
|
|
Pathogenic
(Jun 23, 2019)
|
no assertion criteria provided
Method: research
|
Retinitis pigmentosa
Affected status: yes
Allele origin:
inherited
|
Sharon lab, Hadassah-Hebrew University Medical Center
Accession: SCV001161088.1
First in ClinVar: Feb 16, 2020 Last updated: Feb 16, 2020 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001956422.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001967563.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
|
|
|
Pathogenic
(Dec 28, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Retinitis pigmentosa type 28
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002076600.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001916984.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
|
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Comment:
Comment:
This sequence change creates a premature translational stop signal (p.Arg523*) in the FAM161A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FAM161A are known to be pathogenic (PMID: 20705278, 20705279, 24651477). 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 premature translational stop signal has been observed in individuals with retinitis pigmentosa (PMID: 20705279, 28945494). ClinVar contains an entry for this variant (Variation ID: 38). For these reasons, this variant has been classified as Pathogenic.
Comment:
Nonsense 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: 25525159, 28559085, 31456290, 34426522, 31589614, 28945494, 31345219, 32531858, 32938956, 20705279, 31814694)
Comment:
FAM161A: PM3:Very Strong, PVS1, PM2
Comment:
The p.Arg523Ter variant in FAM161A was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PVS1, PM2, PM3-P. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab.
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:
Variant summary: FAM161A c.1567C>T (p.Arg523X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4.8e-05 in 249446 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in FAM161A causing Retinitis Pigmentosa (4.8e-05 vs 0.00063), allowing no conclusion about variant significance. c.1567C>T has been reported in the literature in multiple individuals affected with Retinitis Pigmentosa. These data indicate that the variant is very likely to be associated with disease. Eight 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.
Comment:
This sequence change creates a premature translational stop signal (p.Arg523*) in the FAM161A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FAM161A are known to be pathogenic (PMID: 20705278, 20705279, 24651477). 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 premature translational stop signal has been observed in individuals with retinitis pigmentosa (PMID: 20705279, 28945494). ClinVar contains an entry for this variant (Variation ID: 38). For these reasons, this variant has been classified as Pathogenic.
Comment:
Nonsense 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: 25525159, 28559085, 31456290, 34426522, 31589614, 28945494, 31345219, 32531858, 32938956, 20705279, 31814694)
Comment:
FAM161A: PM3:Very Strong, PVS1, PM2
Comment:
The p.Arg523Ter variant in FAM161A was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PVS1, PM2, PM3-P. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| The importance of automation in genetic diagnosis: Lessons from analyzing an inherited retinal degeneration cohort with the Mendelian Analysis Toolkit (MATK). | Zampaglione E | Genetics in medicine : official journal of the American College of Medical Genetics | 2022 | PMID: 34906470 |
| Molecular genetic analysis using targeted NGS analysis of 677 individuals with retinal dystrophy. | Jespersgaard C | Scientific reports | 2019 | PMID: 30718709 |
| Identification of the genetic determinants responsible for retinal degeneration in families of Mexican descent. | Villanueva A | Ophthalmic genetics | 2018 | PMID: 28945494 |
| RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. | Xiong HY | Science (New York, N.Y.) | 2015 | PMID: 25525159 |
| Molecular genetics of FAM161A in North American patients with early-onset retinitis pigmentosa. | Venturini G | PloS one | 2014 | PMID: 24651477 |
| Homozygosity mapping reveals null mutations in FAM161A as a cause of autosomal-recessive retinitis pigmentosa. | Bandah-Rozenfeld D | American journal of human genetics | 2010 | PMID: 20705279 |
| Nonsense mutations in FAM161A cause RP28-associated recessive retinitis pigmentosa. | Langmann T | American journal of human genetics | 2010 | PMID: 20705278 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=FAM161A | - | - | - | - |
Text-mined citations for rs202193201 ...
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 Oct 20, 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.