NM_001256789.3(CACNA1F):c.3145C>T (p.Arg1049Trp) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Sep 18, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV001940094.5

Allele description [Variation Report for NM_001256789.3(CACNA1F):c.3145C>T (p.Arg1049Trp)]

NM_001256789.3(CACNA1F):c.3145C>T (p.Arg1049Trp)

Gene:

CACNA1F:calcium voltage-gated channel subunit alpha1 F [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xp11.23

Genomic location:

Preferred name:

NM_001256789.3(CACNA1F):c.3145C>T (p.Arg1049Trp)

HGVS:

NC_000023.11:g.49216473G>A
NG_009095.2:g.21894C>T
NM_001256789.3:c.3145C>TMANE SELECT
NM_001256790.3:c.2983C>T
NM_005183.2:c.3178C>T
NM_005183.4:c.3178C>T
NP_001243718.1:p.Arg1049Trp
NP_001243719.1:p.Arg995Trp
NP_005174.2:p.Arg1060Trp
NC_000023.10:g.49072933G>A

Protein change:

R1049W

Links:

dbSNP: rs2147904860

NCBI 1000 Genomes Browser:

rs2147904860

Molecular consequence:

NM_001256789.3:c.3145C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001256790.3:c.2983C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_005183.4:c.3178C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002178035	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 18, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 9662399, 28373534, 17949918, 28492532
SCV005325657	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Sep 18, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002178035

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 18, 2022)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV005325657

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(Sep 18, 2023)

germline

clinical testing

Citation Link

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

An L-type calcium-channel gene mutated in incomplete X-linked congenital stationary night blindness.

Strom TM, Nyakatura G, Apfelstedt-Sylla E, Hellebrand H, Lorenz B, Weber BH, Wutz K, Gutwillinger N, Rüther K, Drescher B, Sauer C, Zrenner E, Meitinger T, Rosenthal A, Meindl A.

Nat Genet. 1998 Jul;19(3):260-3.

PubMed [citation]

PMID:: 9662399

Trio-based exome sequencing arrests de novo mutations in early-onset high myopia.

Jin ZB, Wu J, Huang XF, Feng CY, Cai XB, Mao JY, Xiang L, Wu KC, Xiao X, Kloss BA, Li Z, Liu Z, Huang S, Shen M, Cheng FF, Cheng XW, Zheng ZL, Chen X, Zhuang W, Zhang Q, Young TL, Xie T, et al.

Proc Natl Acad Sci U S A. 2017 Apr 18;114(16):4219-4224. doi: 10.1073/pnas.1615970114. Epub 2017 Apr 3.

PubMed [citation]

PMID:: 28373534
PMCID:: PMC5402409

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002178035.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This variant is also known as 3145C‚ÜíT, R1049W. This missense change has been observed in individual(s) with congenital stationary night blindness and/or high myopia (PMID: 9662399, 28373534). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1060 of the CACNA1F protein (p.Arg1060Trp). ClinVar contains an entry for this variant (Variation ID: 1410454). 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. Experimental studies have shown that this missense change affects CACNA1F function (PMID: 17949918). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CACNA1F protein function.

#	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

From GeneDx, SCV005325657.1

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

Description

Published functional studies demonstrate a damaging effect to channel currents (Peloquin JB et al., 2007); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33110267, 9662399, 36460718, 28373534, 17949918)

#	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

Last Updated: Oct 8, 2024

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