NM_006269.2(RP1):c.4193C>G (p.Ser1398Cys) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jul 26, 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:: RCV000489003.8

Allele description [Variation Report for NM_006269.2(RP1):c.4193C>G (p.Ser1398Cys)]

NM_006269.2(RP1):c.4193C>G (p.Ser1398Cys)

Gene:

RP1:RP1 axonemal microtubule associated [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

8q12.1

Genomic location:

Preferred name:

NM_006269.2(RP1):c.4193C>G (p.Ser1398Cys)

HGVS:

NC_000008.11:g.54628075C>G
NG_009840.2:g.17009C>G
NM_006269.2:c.4193C>GMANE SELECT
NP_006260.1:p.Ser1398Cys
NC_000008.10:g.55540635C>G
NG_009840.1:g.17009C>G
NM_006269.1:c.4193C>G

Protein change:

S1398C

Links:

dbSNP: rs769270937

NCBI 1000 Genomes Browser:

rs769270937

Molecular consequence:

NM_006269.2:c.4193C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Caenorhabditis briggsae isolate QX1410_ONT chromosome V
Caenorhabditis briggsae isolate QX1410_ONT chromosome V
gi|2179334074|gb|CP090895.1|

Nucleotide
Caenorhabditis briggsae strain AF16 chromosome V
Caenorhabditis briggsae strain AF16 chromosome V
gi|2474537706|gb|CP120834.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000576906	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Uncertain significance (Apr 14, 2017)	germline	clinical testing	Citation Link,
SCV001544427	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 26, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 22052604, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000576906

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Uncertain significance
(Apr 14, 2017)

germline

clinical testing

Citation Link,

SCV001544427

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 26, 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

RP1 and autosomal dominant rod-cone dystrophy: novel mutations, a review of published variants, and genotype-phenotype correlation.

Audo I, Mohand-Saïd S, Dhaenens CM, Germain A, Orhan E, Antonio A, Hamel C, Sahel JA, Bhattacharya SS, Zeitz C.

Hum Mutat. 2012 Jan;33(1):73-80. doi: 10.1002/humu.21640. Epub 2011 Dec 1.

PubMed [citation]

PMID:: 22052604

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, SCV000576906.3

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

Description

The S1398C variant in the RP1 gene has been identified previously in an individual with autosomal dominant retinitis pigmentosa, however, segregation data is limited or absent for other affected family members due to the lack of clinical information provided and insufficient participation by informative family members (Audo et al., 2012). The S1398C variant is observed in 6/66468 (0.009%) alleles from individuals of European non-Finnish background in the ExAC dataset (Lek et al., 2016). The S1398C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved across species, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret S1398C as a variant of uncertain significance.

#	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, SCV001544427.5

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

Description

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 426459). This missense change has been observed in individuals with clinical features of autosomal dominant retinitis pigmentosa (PMID: 22052604; Invitae). This variant is present in population databases (rs769270937, gnomAD 0.009%). This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1398 of the RP1 protein (p.Ser1398Cys).

#	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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