rs62625014

chr4-47937535-G-Achr4-47937535-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PP5_Very_Strong BP4

The NM_001379270.1(CNGA1):c.947C>T(p.Ser316Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00167 in 1,614,178 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S316C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (2 hom.)
• Consequence: CNGA1 NM_001379270.1 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:20
• Conservation: PhyloP100: 9.54

Genes affected

CNGA1 (HGNC:2148): (cyclic nucleotide gated channel subunit alpha 1) The protein encoded by this gene is involved in phototransduction. Along with another protein, the encoded protein forms a cGMP-gated cation channel in the plasma membrane, allowing depolarization of rod photoreceptors. This represents the last step in the phototransduction pathway. Defects in this gene are a cause of retinitis pigmentosa autosomal recessive (ARRP) disease. Multiple transcript variants have been found for this gene. [provided by RefSeq, Oct 2019]

LOC101927157 (HGNC:):

NIPAL1 (HGNC:27194): (NIPA like domain containing 1) Predicted to enable magnesium ion transmembrane transporter activity. Predicted to be involved in magnesium ion transport. Predicted to be integral component of membrane. Predicted to be active in membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PP5: Variant 4-47937535-G-A is Pathogenic according to our data. Variant chr4-47937535-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 16932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-47937535-G-A is described in Lovd as [Likely_pathogenic]. Variant chr4-47937535-G-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.25471663).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNGA1	NM_001379270.1	c.947C>T	p.Ser316Phe	missense_variant	11/11	ENST00000514170.7
LOC101927157	NR_125879.1	n.479-21489G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNGA1	ENST00000514170.7	c.947C>T	p.Ser316Phe	missense_variant	11/11	5	NM_001379270.1	P1

Frequencies

GnomAD3 genomes AF: 0.00112 AC: 171 AN: 152222 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00220

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00110 AC: 274 AN: 249220 Hom.: 0 AF XY: 0.00115 AC XY: 155 AN XY: 135210

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000719

Gnomad FIN exome AF: 0.000510

Gnomad NFE exome AF: 0.00195

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.00173 AC: 2528 AN: 1461838 Hom.: 2 Cov.: 32 AF XY: 0.00169 AC XY: 1232 AN XY: 727216

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000591

Gnomad4 FIN exome AF: 0.000599

Gnomad4 NFE exome AF: 0.00211

Gnomad4 OTH exome AF: 0.00106

GnomAD4 genome AF: 0.00112 AC: 171 AN: 152340 Hom.: 0 Cov.: 32 AF XY: 0.00101 AC XY: 75 AN XY: 74498

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00220

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00174 Hom.: 1

Bravo AF: 0.00104

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000267 AC: 1

ESP6500EA AF: 0.00158 AC: 13

ExAC AF: 0.00103 AC: 124

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00202

EpiControl AF: 0.00178

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:20

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 07, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22995991, 24265693, 25326637, 7479749, 31054281, 28981474, 31456290, 34426522, 31429209, 32531858, 35456422) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 320 of the CNGA1 protein (p.Ser320Phe). This variant is present in population databases (rs62625014, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of retinitis pigmentosa (PMID: 7479749, 24265693, 25326637, 28981474; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as Ser316Phe and p.Ser389Phe. ClinVar contains an entry for this variant (Variation ID: 16932). 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 not expected to disrupt CNGA1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects CNGA1 function (PMID: 7479749). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	CNGA1: PM3:Very Strong, PP1:Strong, PM2:Supporting -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Retinitis pigmentosa Pathogenic:5

Likely pathogenic, no assertion criteria provided	research	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	Apr 01, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 29, 2018	The CNGA1 c.959C>T (p.Ser320Phe) missense variant, also referred to as c.1166C>T (p.Ser389Phe) and p.Ser316Phe, was found in a compound heterozygous state in six probands, including two sibling pairs, with autosomal recessive retinintis pigmentosa (Dryja et al. 1995; Eisenberger et al. 2013; Comander et al. 2017). Control data is unavailable for this variant, which is reported at a frequency of 0.001914 in the European (non-Finnish) population of the Genome Aggregation Database. Dryja et al. (1995) investigated channel function and found the p.Ser389Phe variant was similar to wild type for channel current and open times of the channel, however, the location was found to be intracellular, whereas wild type CNGA1 protein was located at the cell membrane. Based on the evidence, this variant is classified as likely pathogenic for autosomal recessive retinitis pigmentosa. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 11, 2018	The p.Ser320Phe variant in CNGA1 (also described as p.Ser316Phe and p.Ser389Phe in the literature) has been reported in compound heterozygous state in 4 individ uals with autosomal recessive retinitis pigmentosa (RP), and segregated with dis ease in 2 affected relatives from 2 families (Dryja 1995, Eisenberger 2013, Coma nder 2017). In vitro functional studies provide some evidence that the p.Ser320P he variant may impact protein function (Dryja 1995). This variant has been repor ted in ClinVar (Variation ID: 424770) and has been identified in 0.19% (242/1264 08) Of European chromosomes by the Genome Aggregation Database (gnomAD, http://g nomad.broadinstitute.org; dbSNP rs62625014). Please note that this frequency is low enough to be consistent with the frequency of RP in the general population. In summary, although additional studies are required to fully establish its clin ical significance, the p.Ser320Phe variant is likely pathogenic for RP in an aut osomal recessive manner. ACMG/AMP Criteria applied: PM3_Strong; PP1; PS3_Support ing. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 18, 2023	Variant summary: CNGA1 c.947C>T (p.Ser316Phe) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0011 in 249220 control chromosomes, predominantly at a frequency of 0.0019 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in CNGA1 causing Retinitis Pigmentosa phenotype (0.00088), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.947C>T has been reported in the literature in multiple individuals affected with Retinitis Pigmentosa, either at a compound heterozygous with second pathogenic variants or at a homozygous state (examples, Dryja_1995, Lee_CNGA1_2014, Weisschuh_2020). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of frequencies of detecting functional cGMP-activated channel in HEK293 cells and the variant CNGA1 was predominantly retained inside the cell instead of being targeted to the plasma membrane (Dryja_1995). The following publications have been ascertained in the context of this evaluation (PMID: 7479749, 25326637, 32531858). 12 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, no assertion criteria provided	research	Sharon lab, Hadassah-Hebrew University Medical Center	Jun 23, 2019	- -

Retinitis pigmentosa 49 Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 29, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 24, 1995	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 12, 2022	- -
Likely pathogenic, criteria provided, single submitter	research	Ocular Genomics Institute, Massachusetts Eye and Ear	Apr 08, 2021	The CNGA1 c.1166C>T variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2, PP1, PS3, PM3. Based on this evidence we have classified this variant as Likely Pathogenic. -

Macular dystrophy Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Apr 01, 2018

- -

See cases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2016

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PP3,PP5. -

Cone-rod dystrophy Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Apr 01, 2018

- -

Retinitis pigmentosa;C3151059:Retinitis pigmentosa 49 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 04, 2022

- -

Retinal dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Aug 16, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.49
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.25	T;T;T;T;T
MetaSVM	Pathogenic	0.87	D
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-4.0	D;D;.;D;D
REVEL	Pathogenic	0.82
Sift	Benign	0.048	D;D;.;D;D
Sift4G	Uncertain	0.054	T;T;T;T;T
Polyphen		0.15	.;B;.;B;B
Vest4		0.92
MVP		0.97
MPC		0.55
ClinPred		0.056	T
GERP RS		4.8
Varity_R		0.70
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs62625014; hg19: chr4-47939552;