NM_001256789.3(CACNA1F):c.3020G>A (p.Gly1007Glu) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Jul 21, 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:: RCV000483436.3

Allele description [Variation Report for NM_001256789.3(CACNA1F):c.3020G>A (p.Gly1007Glu)]

NM_001256789.3(CACNA1F):c.3020G>A (p.Gly1007Glu)

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.3020G>A (p.Gly1007Glu)

HGVS:

NC_000023.11:g.49217914C>T
NG_009095.2:g.20453G>A
NM_001256789.3:c.3020G>AMANE SELECT
NM_001256790.3:c.2858G>A
NM_005183.4:c.3053G>A
NP_001243718.1:p.Gly1007Glu
NP_001243719.1:p.Gly953Glu
NP_005174.2:p.Gly1018Glu
NC_000023.10:g.49074373C>T
NM_005183.2:c.3053G>A

Protein change:

G1007E

Links:

dbSNP: rs1064794711

NCBI 1000 Genomes Browser:

rs1064794711

Molecular consequence:

NM_001256789.3:c.3020G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001256790.3:c.2858G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_005183.4:c.3053G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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thiB [Erwinia billingiae Eb661]
thiB [Erwinia billingiae Eb661]
Gene ID:90510714

Gene
EbC_07010 AND (alive[prop]) (1)
Gene
potassium voltage-gated channel subfamily A member 2 isoform X1 [Rattus norvegic...
potassium voltage-gated channel subfamily A member 2 isoform X1 [Rattus norvegicus]
gi|1958749293|ref|XP_038957725.1|

Protein
Severe acute respiratory syndrome coronavirus 2 isolate SARS-CoV-2/human/BRA/RJ-...
Severe acute respiratory syndrome coronavirus 2 isolate SARS-CoV-2/human/BRA/RJ-DCVN1/2020, complete genome
gi|1883806255|gb|MT827202.1|

Nucleotide
Type 1 diabetes: Learn More – Types of insulin - InformedHealth.org
Type 1 diabetes: Learn More – Types of insulin - InformedHealth.org

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000569779	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Likely pathogenic (Mar 24, 2016)	germline	clinical testing	Citation Link,
SCV004448900	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 21, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 12111638, 17949918, 19578023, 23714322, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000569779

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Likely pathogenic
(Mar 24, 2016)

germline

clinical testing

Citation Link,

SCV004448900

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 21, 2023)

germline

clinical testing

PubMed (5)
[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

Thirty distinct CACNA1F mutations in 33 families with incomplete type of XLCSNB and Cacna1f expression profiling in mouse retina.

Wutz K, Sauer C, Zrenner E, Lorenz B, Alitalo T, Broghammer M, Hergersberg M, de la Chapelle A, Weber BH, Wissinger B, Meindl A, Pusch CM.

Eur J Hum Genet. 2002 Aug;10(8):449-56.

PubMed [citation]

PMID:: 12111638

Functional analysis of congenital stationary night blindness type-2 CACNA1F mutations F742C, G1007R, and R1049W.

Peloquin JB, Rehak R, Doering CJ, McRory JE.

Neuroscience. 2007 Dec 5;150(2):335-45. Epub 2007 Sep 14.

PubMed [citation]

PMID:: 17949918

See all PubMed Citations (5)

Details of each submission

From GeneDx, SCV000569779.4

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

Description

The G1018E variant in the CACNA1F gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G1018E 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. This substitution occurs at a position where amino acids with similar properties to Glycine are tolerated across species; however, the G1018E variant results in a replacement of a polar, uncharged Glycine with a larger, acidic Glutamic Acid residue. In silico analysis predicts this variant is probably damaging to the protein structure/function, and protein modeling studies suggest that the substitution of Glycine-1018 with a larger amino acid disrupts calcium channel structure and function (Stockner and Koschak, 2015). A missense variant in the same residue (G1018R) has been reported in the Human Gene Mutation Database in association with congenital stationary night blindness (Stenson et al., 2014), supporting the functional importance of this residue of the protein. The G1018E variant is a strong candidate for a pathogenic variant, however, the possibility it may be a rare benign variant cannot be excluded.

#	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, SCV004448900.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. ClinVar contains an entry for this variant (Variation ID: 420802). This missense change has been observed in individual(s) with clinical features of inherited retinal dystrophy (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 1018 of the CACNA1F protein (p.Gly1018Glu). This variant disrupts the p.Gly1018 amino acid residue in CACNA1F. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12111638, 17949918, 19578023, 23714322). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.

#	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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