NM_016492.5(RANGRF):c.437C>T (p.Pro146Leu) AND Cardiac arrhythmia

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Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jul 10, 2017
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000467051.2

Allele description

NM_016492.5(RANGRF):c.437C>T (p.Pro146Leu)

Genes:

RANGRF:RAN guanine nucleotide release factor [Gene - OMIM - HGNC]
SLC25A35:solute carrier family 25 member 35 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17p13.1

Genomic location:

Preferred name:

NM_016492.5(RANGRF):c.437C>T (p.Pro146Leu)

HGVS:

NC_000017.11:g.8289588C>T
NG_028189.1:g.5938C>T
NM_001177801.2:c.437C>T
NM_001177802.2:c.*27C>T
NM_001320871.2:c.*28G>A
NM_001320872.2:c.*28G>A
NM_001330127.2:c.351+174C>T
NM_016492.5:c.437C>TMANE SELECT
NM_201520.3:c.*28G>A
NP_001171272.1:p.Pro146Leu
NP_057576.2:p.Pro146Leu
NC_000017.10:g.8192906C>T
NM_016492.4:c.437C>T
NR_135483.2:n.1573G>A
NR_135484.2:n.1585G>A

Protein change:

P146L

Links:

dbSNP: rs765772294

NCBI 1000 Genomes Browser:

rs765772294

Molecular consequence:

NM_001177802.2:c.*27C>T - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001320871.2:c.*28G>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001320872.2:c.*28G>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_201520.3:c.*28G>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001330127.2:c.351+174C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001177801.2:c.437C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_016492.5:c.437C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_135483.2:n.1573G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_135484.2:n.1585G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Cardiac arrhythmia
Identifiers:: MedGen: C0003811

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000541084	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 10, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000541084

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 10, 2017)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

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

Citations

PubMed

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):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV000541084.2

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

Description

This sequence change replaces proline with leucine at codon 146 of the RANGRF protein (p.Pro146Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. It also falls at the last nucleotide of exon 4 of the RANGRF mRNA. This variant is present in population databases (rs765772294, ExAC 0.01%) but has not been reported in the literature in individuals with a RANGRF-related disease. 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, but these predictions have not been confirmed by published functional studies. Nucleotide substitutions at the last nucleotide of the exon are relatively common causes of aberrant splicing (PMID: 17576681) but according to multiple splice site algorithms this particular variant is not predicted to significantly affect splicing. These predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function and mRNA splicing. It has been classified as a Variant of Uncertain Significance.

#	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: Feb 26, 2022

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