1-94062608-G-T

Variant names:

• chr1-94062608-G-T
• NM_000350.3:c.1906C>A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_000350.3(ABCA4):​c.1906C>A​(p.Gln636Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,864 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q636H) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ABCA4 NM_000350.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 10.0

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_000350.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-94062606-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 99097.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.862
• PP5: Variant 1-94062608-G-T is Pathogenic according to our data. Variant chr1-94062608-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 2202801.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-94062608-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA4	NM_000350.3	c.1906C>A	p.Gln636Lys	missense_variant	Exon 13 of 50	ENST00000370225.4	NP_000341.2
ABCA4	NM_001425324.1	c.1906C>A	p.Gln636Lys	missense_variant	Exon 13 of 49		NP_001412253.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4	c.1906C>A	p.Gln636Lys	missense_variant	Exon 13 of 50	1	NM_000350.3	ENSP00000359245.3
ABCA4	ENST00000649773.1	c.1906C>A	p.Gln636Lys	missense_variant	Exon 13 of 19			ENSP00000496882.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461864 Hom.: 0 Cov.: 37 AF XY: 0.00 AC XY: 0 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Sep 06, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gln636 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9781034, 19217903, 24677105, 28327576). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This missense change has been observed in individual(s) with ABCA4-related conditions (PMID: 31543898, 31814693). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 636 of the ABCA4 protein (p.Gln636Lys). -

Cone-rod dystrophy 3 Pathogenic:1

Dec 29, 2023

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.84 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.70 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported to be associated with ABCA4 related disorder (ClinVar ID: VCV002202801 /PMID: 26780318). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 31814693). A different missense change at the same codon (p.Gln636His) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000099097 /PMID: 9781034). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D;.
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Pathogenic	3.3	M;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.5	D;.
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0060	D;.
Sift4G	Uncertain	0.012	D;.
Polyphen		0.86	P;.
Vest4		0.90
MutPred		0.56		Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);
MVP		0.97
MPC		0.52
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.89
gMVP		0.90

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: chr1-94528164;