VCV000866263.7 - ClinVar

NM_178857.6(RP1L1):c.3595T>G (p.Ser1199Ala)

Germline

Classification

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.

(4)

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.

Conflicting classifications of pathogenicity
Likely pathogenic(1); Uncertain significance(3)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_178857.6(RP1L1):c.3595T>G (p.Ser1199Ala)

Variation ID: 866263 Accession: VCV000866263.7

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 8p23.1 8: 10468013 (GRCh37) [ NCBI UCSC ] 8: 10610503 (GRCh38) [ 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 18, 2020	Jul 7, 2024	May 13, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_178857.6:c.3595T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_849188.4:p.Ser1199Ala	missense
NC_000008.11:g.10610503A>C
NC_000008.10:g.10468013A>C
NG_028035.1:g.49605T>G

Protein change

S1199A

Other names

NM_178857.6(RP1L1):c.3595T>G
p.Ser1199Ala

Canonical SPDI

NC_000008.11:10610502:A:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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

dbSNP: rs1797825562 VarSome

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
Gene	OMIM	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.
RP1L1		-	-	GRCh38 GRCh38 GRCh37	1342	1471

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.
Retinal dystrophy	Likely pathogenic (1)	criteria provided, single submitter	Jan 15, 2019	RCV001074121.2
not provided	Uncertain significance (1)	criteria provided, single submitter	Dec 23, 2019	RCV001576856.3
See cases	Uncertain significance (1)	criteria provided, single submitter	Dec 1, 2021	RCV004584423.1
Occult macular dystrophy	Uncertain significance (1)	criteria provided, single submitter	May 13, 2024	RCV004556076.1

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.
Likely pathogenic (Jan 15, 2019)	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Retinal dystrophy Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV001239690.1 First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 Comment: My Retina Tracker patient
Uncertain significance (Dec 23, 2019)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001804121.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021	Comment: Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does … (more) Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge (less)
Uncertain Significance (May 13, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Occult macular dystrophy (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV005045266.1 First in ClinVar: May 26, 2024 Last updated: May 26, 2024	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/257445f8-cf1e-4747-a77a-dc9b38697310 Comment: The heterozygous p.Ser1199Ala variant in RP1L1 was identified by our study in one individual with occult macular dystrophy. This variant is assumed de novo in … (more) The heterozygous p.Ser1199Ala variant in RP1L1 was identified by our study in one individual with occult macular dystrophy. This variant is assumed de novo in the individual, but maternity and paternity have not been confirmed. This variant was absent from large population studies. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. This variant has been reported in ClinVar (Variation ID:866263) and has been interpreted as likely pathogenic and uncertain significance by Blueprint Genetics, GeneDx, and Muenster University Hospital. Two additional likely pathogenic variants, resulting in a different amino acid change at the same position, p.Ser1199Cys and p.Ser1199Pro, have been reported in association with disease in the literature, slightly supporting that a change at this position may not be tolerated (PMID: 24838559). In summary, the clinical significance of the p.Ser1199Ala variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PM5 (Richards 2015). (less)
Uncertain significance (Dec 01, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	see cases Affected status: yes Allele origin: unknown	Institute of Human Genetics, University Hospital Muenster Accession: SCV002577909.2 First in ClinVar: Oct 08, 2022 Last updated: Jul 07, 2024	Comment: ACMG categories: PM2,PP3 Number of individuals with the variant: 1 Clinical Features: Macular dystrophy (present) Age: 10-19 years Sex: male Tissue: blood

Comment:

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

Comment:

The heterozygous p.Ser1199Ala variant in RP1L1 was identified by our study in one individual with occult macular dystrophy. This variant is assumed de novo in the individual, but maternity and paternity have not been confirmed. This variant was absent from large population studies. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. This variant has been reported in ClinVar (Variation ID:866263) and has been interpreted as likely pathogenic and uncertain significance by Blueprint Genetics, GeneDx, and Muenster University Hospital. Two additional likely pathogenic variants, resulting in a different amino acid change at the same position, p.Ser1199Cys and p.Ser1199Pro, have been reported in association with disease in the literature, slightly supporting that a change at this position may not be tolerated (PMID: 24838559). In summary, the clinical significance of the p.Ser1199Ala variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PM5 (Richards 2015).

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/257445f8-cf1e-4747-a77a-dc9b38697310	-	-	-	-

Text-mined citations for rs1797825562 ...

These 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 25, 2024

ClinVar Genomic variation as it relates to human health

NM_178857.6(RP1L1):c.3595T>G (p.Ser1199Ala)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1797825562 ...