rs397516319

Variant names:

• chr11-77205509-T-G
• rs397516319
• NM_000260.4:c.5528T>G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_000260.4(MYO7A):​c.5528T>G​(p.Leu1843Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000005 in 1,599,160 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 7.64

Genes affected

MYO7A (HGNC:7606): (myosin VIIA) This gene is a member of the myosin gene family. Myosins are mechanochemical proteins characterized by the presence of a motor domain, an actin-binding domain, a neck domain that interacts with other proteins, and a tail domain that serves as an anchor. This gene encodes an unconventional myosin with a very short tail. Defects in this gene are associated with the mouse shaker-1 phenotype and the human Usher syndrome 1B which are characterized by deafness, reduced vestibular function, and (in human) retinal degeneration. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a domain MyTH4 2 (size 149) in uniprot entity MYO7A_HUMAN there are 15 pathogenic changes around while only 5 benign (75%) in NM_000260.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.959

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.5528T>G	p.Leu1843Arg	missense_variant	Exon 40 of 49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.5528T>G	p.Leu1843Arg	missense_variant	Exon 40 of 49	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.5414T>G	p.Leu1805Arg	missense_variant	Exon 40 of 49	1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.5381T>G	p.Leu1794Arg	missense_variant	Exon 41 of 50	1		ENSP00000386635.2
MYO7A	ENST00000458169.2	c.2954T>G	p.Leu985Arg	missense_variant	Exon 20 of 29	1		ENSP00000417017.2
MYO7A	ENST00000670577.1	n.*126T>G		non_coding_transcript_exon_variant	Exon 23 of 32			ENSP00000499323.1
MYO7A	ENST00000670577	n.*126T>G		3_prime_UTR_variant	Exon 23 of 30			ENSP00000499323.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152118 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000484 AC: 7 AN: 1447042 Hom.: 0 Cov.: 32 AF XY: 0.00000696 AC XY: 5 AN XY: 718414

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000633

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152118 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74308

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Jun 21, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Pathogenic. The Leu1843Arg variant in MYO7A has not been reported in the literature nor previously identifi ed by our laboratory. This residue is conserved across species and computational analyses (biochemical amino acid change, homology, PolyPhen2, SIFT) suggest tha t the Leu1843Arg variant may impact the protein. However, this information is no t predictive enough to assume pathogenicity. The presence of this variant in com bination with a pathogenic MYO7A variant and in an individual with clinical feat ures of hearing loss, increases the likelihood that the Leu1843Arg variant is pa thogenic. However, it should be noted that this lab has only sequenced MYO7A in 22 Black probands and no Black healthy controls. In addition, healthy control in formation is limited in either public databases or scientific literature, such t hat the full spectrum of benign variation has not yet been defined for this gene . Future analysis could reveal that the Leu1843Arg variant is common in this pop ulation and therefore unlikely to be pathogenic. In summary, the clinical signif icance of this variant cannot be determined with certainty at this time. -

Inborn genetic diseases Uncertain:1

Mar 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5528T>G (p.L1843R) alteration is located in exon 40 (coding exon 39) of the MYO7A gene. This alteration results from a T to G substitution at nucleotide position 5528, causing the leucine (L) at amino acid position 1843 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Usher syndrome type 1B Uncertain:1

Sep 16, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Uncertain:1

Jan 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1843 of the MYO7A protein (p.Leu1843Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with MYO7A-related conditions. ClinVar contains an entry for this variant (Variation ID: 43285). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MYO7A protein function with a positive predictive value of 95%. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;.;.;D
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	3.2	M;.;.;.
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-5.3	D;D;D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		0.76	P;.;.;.
Vest4		0.99
MutPred		0.82		Gain of methylation at L1843 (P = 0.048);.;.;.;
MVP		0.98
MPC		0.39
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.99
gMVP		0.85

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: rs397516319; hg19: chr11-76916554;