NM_000350.3:c.926C>A

Variant names:

• chr1-94080651-G-T
• NM_000350.3:c.926C>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP5_Moderate

The NM_000350.3(ABCA4):​c.926C>A​(p.Pro309Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. P309R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ABCA4 NM_000350.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.97

Genes affected

ABCA4 (HGNC:34): (ATP binding cassette subfamily A member 4) The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intracellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the ABC1 subfamily. Members of the ABC1 subfamily comprise the only major ABC subfamily found exclusively in multicellular eukaryotes. This protein is a retina-specific ABC transporter with N-retinylidene-PE as a substrate. It is expressed exclusively in retina photoreceptor cells, and the gene product mediates transport of an essental molecule, all-trans-retinal aldehyde (atRAL), across the photoreceptor cell membrane. Mutations in this gene are found in patients diagnosed with Stargardt disease, a form of juvenile-onset macular degeneration. Mutations in this gene are also associated with retinitis pigmentosa-19, cone-rod dystrophy type 3, early-onset severe retinal dystrophy, fundus flavimaculatus, and macular degeneration age-related 2. [provided by RefSeq, Sep 2019]

LOC124904222 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-94080651-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 99513.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 1-94080651-G-T is Pathogenic according to our data. Variant chr1-94080651-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2698883.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA4	NM_000350.3	c.926C>A	p.Pro309Gln	missense_variant	Exon 8 of 50	ENST00000370225.4	NP_000341.2
ABCA4	NM_001425324.1	c.926C>A	p.Pro309Gln	missense_variant	Exon 8 of 49		NP_001412253.1
LOC124904222	XR_007066231.1	n.203-3078G>T		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4	c.926C>A	p.Pro309Gln	missense_variant	Exon 8 of 50	1	NM_000350.3	ENSP00000359245.3
ABCA4	ENST00000649773.1	c.926C>A	p.Pro309Gln	missense_variant	Exon 8 of 19			ENSP00000496882.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Nov 25, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 309 of the ABCA4 protein (p.Pro309Gln). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ABCA4-related conditions. 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 ABCA4 protein function with a positive predictive value of 95%. This variant disrupts the p.Pro309 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25066811; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Uncertain	0.72	D;.
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.75	T;T
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.44	T;T
MetaSVM	Uncertain	0.41	D
MutationAssessor	Benign	1.8	L;.
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-2.8	D;.
REVEL	Uncertain	0.53
Sift	Uncertain	0.0040	D;.
Sift4G	Benign	0.31	T;.
Polyphen		0.94	P;.
Vest4		0.76
MutPred		0.42		Loss of catalytic residue at G308 (P = 0.0749);Loss of catalytic residue at G308 (P = 0.0749);
MVP		0.94
MPC		0.20
ClinPred		0.53	D
GERP RS		5.8
Varity_R		0.16
gMVP		0.74

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-94546207;