6-76018812-A-G

Position:

• chr6-76018812-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM5 PP3_Moderate PP5

The NM_001563.4(IMPG1):​c.713T>C​(p.Leu238Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L238R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IMPG1 NM_001563.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 5.37

Genes affected

IMPG1 (HGNC:6055): (interphotoreceptor matrix proteoglycan 1) This gene encodes a protein that is a major component of the retinal interphotoreceptor matrix. The encoded protein is a proteoglycan that is thought to play a role in maintaining viability of photoreceptor cells and in adhesion of the neural retina to the retinal pigment epithelium. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-76018812-A-C is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.883
• PP5: Variant 6-76018812-A-G is Pathogenic according to our data. Variant chr6-76018812-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 865770.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}. Variant chr6-76018812-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IMPG1	NM_001563.4	c.713T>C	p.Leu238Pro	missense_variant	7/17	ENST00000369950.8	NP_001554.2
IMPG1	NM_001282368.2	c.479T>C	p.Leu160Pro	missense_variant	6/16		NP_001269297.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IMPG1	ENST00000369950.8	c.713T>C	p.Leu238Pro	missense_variant	7/17	1	NM_001563.4	ENSP00000358966	P2
IMPG1	ENST00000611179.4	c.479T>C	p.Leu160Pro	missense_variant	6/16	5		ENSP00000481913	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Retinal dystrophy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Aug 31, 2018

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 08, 2023

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. This variant disrupts the p.Leu238 amino acid residue in IMPG1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23993198). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 865770). This missense change has been observed in individuals with clinical features of vitelliform macular dystrophy (PMID: 28644393; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 238 of the IMPG1 protein (p.Leu238Pro). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.041	T;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.035	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.4	M;.
MutationTaster	Benign	0.95	D;D
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.1	D;.
REVEL	Uncertain	0.34
Sift	Uncertain	0.0020	D;.
Sift4G	Uncertain	0.0030	D;D
Polyphen		0.99	D;.
Vest4		0.85
MutPred		0.65		Gain of disorder (P = 0.0214);.;
MVP		0.72
MPC		0.10
ClinPred		0.97	D
GERP RS		6.1
Varity_R		0.76
gMVP		0.82

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: rs713993045; hg19: chr6-76728529;