NM_000350.3(ABCA4):c.6379T>C (p.Ser2127Pro) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Jul 31, 2023
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001755001.4

Allele description [Variation Report for NM_000350.3(ABCA4):c.6379T>C (p.Ser2127Pro)]

NM_000350.3(ABCA4):c.6379T>C (p.Ser2127Pro)

Gene:

ABCA4:ATP binding cassette subfamily A member 4 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p22.1

Genomic location:

Preferred name:

NM_000350.3(ABCA4):c.6379T>C (p.Ser2127Pro)

HGVS:

NC_000001.11:g.94001009A>G
NG_009073.1:g.125141T>C
NG_009073.2:g.125139T>C
NM_000350.3:c.6379T>CMANE SELECT
NM_001425324.1:c.6157T>C
NP_000341.2:p.Ser2127Pro
NP_001412253.1:p.Ser2053Pro
NC_000001.10:g.94466565A>G
NM_000350.2:c.6379T>C

Protein change:

S2053P

Links:

dbSNP: rs2100993895

NCBI 1000 Genomes Browser:

rs2100993895

Molecular consequence:

NM_000350.3:c.6379T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001425324.1:c.6157T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001995817	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Jan 28, 2020)	germline	clinical testing	Citation Link,
SCV004411198	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jul 31, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 32619608, 32783370, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001995817

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Jan 28, 2020)

germline

clinical testing

Citation Link,

SCV004411198

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jul 31, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Genotype-Phenotype Correlations in a Spanish Cohort of 506 Families With Biallelic ABCA4 Pathogenic Variants.

Del Pozo-Valero M, Riveiro-Alvarez R, Blanco-Kelly F, Aguirre-Lamban J, Martin-Merida I, Iancu IF, Swafiri S, Lorda-Sanchez I, Rodriguez-Pinilla E, Trujillo-Tiebas MJ, Jimenez-Rolando B, Carreño E, Mahillo-Fernandez I, Rivolta C, Corton M, Avila-Fernandez A, Garcia-Sandoval B, Ayuso C.

Am J Ophthalmol. 2020 Nov;219:195-204. doi: 10.1016/j.ajo.2020.06.027. Epub 2020 Jun 30.

PubMed [citation]

PMID:: 32619608

The genetic landscape of inherited eye disorders in 74 consecutive families from the United Arab Emirates.

Méjécase C, Kozak I, Moosajee M.

Am J Med Genet C Semin Med Genet. 2020 Sep;184(3):762-772. doi: 10.1002/ajmg.c.31824. Epub 2020 Aug 11.

PubMed [citation]

PMID:: 32783370
PMCID:: PMC8432150

See all PubMed Citations (3)

Details of each submission

From GeneDx, SCV001995817.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown; Has not been previously published as pathogenic or benign to our knowledge

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004411198.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

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. 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. This variant disrupts the p.Ser2127 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 32619608, 32783370). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 1312247). This missense change has been observed in individual(s) with clinical features of Stargardt disease (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 2127 of the ABCA4 protein (p.Ser2127Pro).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

ClinVar

Relating variation to medicine