chr8-54621481-T-C

Position:

• chr8-54621481-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_006269.2(RP1):​c.515T>C​(p.Leu172Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L172R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: RP1 NM_006269.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.14

Genes affected

RP1 (HGNC:10263): (RP1 axonemal microtubule associated) This gene encodes a member of the doublecortin family. The protein encoded by this gene contains two doublecortin domains, which bind microtubules and regulate microtubule polymerization. The encoded protein is a photoreceptor microtubule-associated protein and is required for correct stacking of outer segment disc. This protein and the RP1L1 protein, another retinal-specific protein, play essential and synergistic roles in affecting photosensitivity and outer segment morphogenesis of rod photoreceptors. Because of its response to in vivo retinal oxygen levels, this protein was initially named ORP1 (oxygen-regulated protein-1). This protein was subsequently designated RP1 (retinitis pigmentosa 1) when it was found that mutations in this gene cause autosomal dominant retinitis pigmentosa. Mutations in this gene also cause autosomal recessive retinitis pigmentosa. Transcript variants resulted from an alternative promoter and alternative splicings have been found, which overlap the current reference sequence and has several exons upstream and downstream of the current reference sequence. However, the biological validity and full-length nature of some variants cannot be determined at this time.[provided by RefSeq, Sep 2010]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a domain Doublecortin 2 (size 79) in uniprot entity RP1_HUMAN there are 18 pathogenic changes around while only 5 benign (78%) in NM_006269.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-54621481-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 195261.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Uncertain_significance=2}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.878

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RP1	NM_006269.2	c.515T>C	p.Leu172Pro	missense_variant	2/4	ENST00000220676.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RP1	ENST00000220676.2	c.515T>C	p.Leu172Pro	missense_variant	2/4	1	NM_006269.2
RP1	ENST00000637698.1	c.515T>C	p.Leu172Pro	missense_variant	2/29	5		P1
RP1	ENST00000636932.1	c.515T>C	p.Leu172Pro	missense_variant	2/23	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461820 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727218

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 12, 2023

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 172 of the RP1 protein (p.Leu172Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RP1-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Leu172 amino acid residue in RP1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22334370, 28041643, 29068140, 32565670). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	.;D;.
Eigen	Uncertain	0.36
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.55	T;T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Pathogenic	3.2	.;M;.
MutationTaster	Benign	0.96	N
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-5.8	.;D;.
REVEL	Pathogenic	0.68
Sift	Benign	0.044	.;D;.
Sift4G	Uncertain	0.0020	.;D;.
Polyphen		1.0	.;D;.
Vest4		0.91
MVP		0.94
MPC		0.27
ClinPred		0.96	D
GERP RS		4.0
Varity_R		0.92
gMVP		0.95

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: rs180729424; hg19: chr8-55534041;