NM_000350.3(ABCA4):c.4945C>T (p.Pro1649Ser) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Nov 18, 2021
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001812786.18

Allele description [Variation Report for NM_000350.3(ABCA4):c.4945C>T (p.Pro1649Ser)]

NM_000350.3(ABCA4):c.4945C>T (p.Pro1649Ser)

Genes:

ABCA4:ATP binding cassette subfamily A member 4 [Gene - OMIM - HGNC]
LOC126805793:CDK7 strongly-dependent group 2 enhancer GRCh37_chr1:94486302-94487501 [Gene]

Variant type:

single nucleotide variant

Cytogenetic location:

1p22.1

Genomic location:

Preferred name:

NM_000350.3(ABCA4):c.4945C>T (p.Pro1649Ser)

HGVS:

NC_000001.11:g.94021313G>A
NG_009073.1:g.104837C>T
NG_009073.2:g.104835C>T
NG_082117.1:g.668G>A
NM_000350.3:c.4945C>TMANE SELECT
NM_001425324.1:c.4723C>T
NP_000341.2:p.Pro1649Ser
NP_001412253.1:p.Pro1575Ser
NC_000001.10:g.94486869G>A
NM_000350.2:c.4945C>T

Protein change:

P1575S

Links:

dbSNP: rs886046563

NCBI 1000 Genomes Browser:

rs886046563

Molecular consequence:

NM_000350.3:c.4945C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001425324.1:c.4723C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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4-phosphopantoate--beta-alanine ligase [Halorutilales archaeon Cl-col2-1]
4-phosphopantoate--beta-alanine ligase [Halorutilales archaeon Cl-col2-1]
gi|2801084059|gnl|PRJNA949680|ACEU6 45|gb|XGI83651.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001472423	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Uncertain significance (Nov 28, 2019)	germline	clinical testing	Citation Link,
SCV002158906	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 18, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001472423

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process)

Uncertain significance
(Nov 28, 2019)

germline

clinical testing

Citation Link,

SCV002158906

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 18, 2021)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

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

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001472423.1

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

Description

The ABCA4 p.Pro1649Ser variant (rs886046563), to our knowledge, has not been reported in the medical literature; however, this variant is listed in the ClinVar database (Variation ID: 298231). This variant is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The proline at codon 1649 is highly conserved (Alamut v.2.11) but computational analyses (SIFT: Tolerated, PolyPhen-2: Possibly damaging) predict conflicting effects of this variant on protein structure/function. Due to limited information, the clinical significance of the p.Pro1649Ser variant is uncertain at this time.

#	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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002158906.3

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

Description

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1649 of the ABCA4 protein (p.Pro1649Ser). This variant is present in population databases (no rsID available, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with ABCA4-related conditions. ClinVar contains an entry for this variant (Variation ID: 298231). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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.

#	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: Oct 26, 2024

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